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Targeted Protein Degradation Explained | Drug Discovery & DDS

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TECHNOLOGY EXPLAINER

Targeted Protein Degradation
— From drugs that inhibit proteins to drugs that dispose of them

The target protein decomposition in tor (PROTAC) isCarry on the cell’s own decomposition device rather than blocking the work of proteinLow。. to the next target without being consumed,Like catal sHome The price is the size of the ,PROTAC-type oral agent approved by the FDA in May 2026, with a weight of 723.90 gDutch It is more than 500 as a guide for oral medicine.

Composition: FDA approval attachment and Drugs@FDA, Nobel Foundation announcement, ClinicalTrials.gov, Nature Reviews Drug /Science/PNAS/Adv Drug Deliv Rev

On the dark side, a thin component with different shapes of both ends bridges two different shapes simultaneously
Concept diagram (AI generation image).It is expressed as an atmosphere of the idea that "Take a separate opponent at both ends and approach two".It does not indicate the actual structure or product.
Composition of this article
  1. What is a target protein decomposition?
  2. Ubiquitin-proteasome system - mechanism of 'disposal' of cells
  3. Two types - PROTAC and thio-adhesives
  4. Differences from low- in tors - from occupancy to events
  5. Perspective 1: This is a catal rather than a drug
  6. E3 Riggerze - There are more than 600 types, but two are mainly used
  7. Uptake: How much swelling is uptake
  8. Oral Absorption Wall - approved two-agent attachments
  9. Material Technician Perspective 2: Filled with Insufficient Solubility
  10. Status of development and approval (reco zed by regulatory officials)
  11. Glossary/Reference Materials/Reference Table
Terms of Use

Facts= Contents described in the publication material (with source link)
The calculation of this paper= The value calculated based on the specified premise
Undetermined / Future= Items that have not been confirmed as a plan and goal
In addition to this, reading on structure arrangement, material and formulation design is"Description"is distinguished.

Medical care

About this articleExplanation of chemical, material and preparation technologyHome not to evaluate the effects and safety of the treatment, No medical advice. It is not recommended for certain medicines or treatments, or for the inferiority of the drug. The number of approvals, compositions, and pharmacokinetics quotes only those listed in the FDA publication. where the usage and dosage are described,citation of the attachment to determine the drug on the preparation designIt is not recommended to use.

1. What is the target protein decomposition?

  • What to do:Békés et al target protein decomposition (TPD)New treatment modalities with the possibility of working on protein that causes the disease, which was historically very difficult to target in conventional low-dose therapiesdefinedFacts。Dissolve into cells rather than blocking protein functions
  • How to:PROTAC isOne end binds to target protein (POI), and the other end calls E3 ubiquitin ligaseHome both simultaneouslyDecomposition of POI by ubiquitin and subsequent ubiquitin-proteasome (UPS)HomePROTAC is recycled and targets the following POIsContact UsFacts
  • What’s different:Comment"This catal、-type mechanism of action and event-driven pharmacy distinguish PROTAC from a classic in、tor"and classic in torsThe relationship between POI is one-to-one, and its pharmacology is driven by chemical reporters and usually interactions with catalytic sites.Comparing withFacts
The best line in this article

The essence of this technology is not the mechanism of action, but the tradeoff. To grab two proteins simultaneously,Contains two ligands and linkers into onerequired. As a result, the weight exceeds the approximation of oral medicine. Veppanu, approved by the FDA on May 1st, 2026, is attached "Hetero2 Functional Protein Decomposition Derivatives" and "E、gen Receptor Binding Domains"and weight 723.90HomeFactsHome Lipinski et al. "rule of 5"weight 500CommentFacts。 This excess is the center of formulation and physical design in this field.(This article)

2. Ubikitin-Proteasom system - The mechanism of "disposal" of cells

This technology borrows cells originallyProtein disposal lineComment Nobel Chemical Award 2004

Nobel Foundation (October 6, 2004)

Royal Swedish Academy of Sciences Awarded Nobel Prize 2004Discovery of protein decomposition through ubiquitinby Awarded to Aaron Chicanover, Abram Herschko and Arwin RoseFacts。

Presentations are described below."The decomposition is not discriminatory, but occurs through finely controlled processes. In other words, at that time, a protein's tag, dramatically speaking, the protein's death is given. Proteins tagged are sent to the cell’s ‘disposal device’ i.e. proteins, which are cut into small pieces and destroyed.Facts

“This tag binds to the proteins to be destroyed, accompanying the protein som, which is recognized as keys and tablets, and informs that the protein goes to decomposition. Just before the protein is pushed into the protein som, the tag is removed and re-bound.Facts

Békés et al. organizes this process in the enzymatic steps. “proteins are targeted for decomposition by proteasomes in the three-step process of tag activation. (E1), tag binding. (E2), and finally tag-protein ligase (E3). E3 supervises the movement of tags to target proteins.FactsHome and“Human genomes are estimated to code over 600 E3 ligases, each of which has a specificity for the partial set of different proteins.”Facts。

Disposal line of cells and decomposition in the disposal line (conceptual diagram) Upper = Mechanism of Cell Original / Lower = Decomposition Inductor E1 E2 E3 Target protein pro Ubi Enzyme activated Ubi Conveying Enzyme Which protein Decide whether to apply More than 600 types Ubikitin tag attached After removing the tag Disassemble Decomposition in catalysts: E3 and target proteins are forced "Trading" that does not occur in the combination of the game, artificially established After the target is decom , the decomposition inductor is removed and turned to the next target ( Catalytic action mechanism) = "dispose" instead of "extract" * E1, E2, E3, E3 ligase, catalytic action mechanism and recycle are based on Békés et al (2022). * The BTI tag is removed immediately before disassembly and recycled according to the Nobel Foundation's 2004 presentation [Reference Material 2]. * Figures are imitation and do not indicate the shape or size of the。.
Fig. 1 Concept diagram (vector drawing).E1, E2, E3, E3, E3, E3, E3, E3, catalytic action mechanism, Békés et al (2022) [Reference Material 1], Ubiquitin's tag and Proteasome's description is based on Nobel Foundation's 2004 press release [Reference Material 2].The figure is imitation and does not indicate the shape, size, and number of。s.

3. Two types: PROTAC and ZINC adhesive

There are two types of decomposition inductors: PROTACHomeglue ( glue)Comment

Description: What is adhesive?

Békés‘The ZINC adhesive, which is considered to be an accidental discovery that saridomide and its affinity work as a decomposition derivative, constitutes another important treatment class.’HOME "It's not a heterogeneous function like PROTACs, but adhesive increases protein-to-protein interaction (PPI) between ligase and potential substrates to improve biotinization of target proteins."ExplainFacts。

The combination value is different.“Mole、 adhesives can strengthen the formation of E3 ligase and target complexes by in、 such as wedges on the surface between proteins.”Facts。

The order of discovery was also opposite."Here, decomposition in adhesive inhibitors has been found behind. In other words, the mechanism of action of cell injuries such as salidomide has been identified after FDA approval.Facts。

until you find the target of salidomide

The contents of "Discovering Back、" are written in two papers.

  • 2010 Science）："We identified Celebron (CRBN) as a salidomide binding protein. CRBN forms E3 ubiquitin ligase complex with DDB1 and Cul4A.Facts
  • 2014 (Krönke et al, Science）："By using quantitative proteomics, lenalidomide was found that the two lymphatic transfer factors IKZF1 and IKZF3 cause selective biotinization and decomposition by CRBN-CRL4 ubiquitin ligase.and conclusions"These findings reveal the selective decomposition of specific targets by altering the activity of E3 ubiquitin ligase, which has not been known until now in the pharmaceutical drug.Facts

This mechanism is written in the attachment of approved products. Attachments for Rebragin (Renaidus) "The cell-level activity of lenalidomide is mediated through its target Celebron (constituent of the Cul4A E3 ubiquitin ligase complex). In vitro, under the presence of the drug, the substrate protein (including Aiolos, Ikaros, CK1α) becomes ubiquitinated and subsequent decomposition targets.Facts。

PROTAC side is designed from the beginning

PROTAC, one of which, in 2001, demonstrated concepts. SakamotoPNAS) s are:Facts。

(Sakamoto et al 2001)

"We tried to target protein to SCF complexes artificially for biotinization and decomposition.Home"Mechas Protac-1Home"One domain of Protac-1 includes IκBα phosphate peptides recognized by F-box protein β-TRCP, and other domains consist of ovalicin."Facts

Result"MetAP-2 is connected to SCF (β-TRCP), which indicates that it is decom) by protac-1."It wasFacts。

Békés et al report this 2001In vitro concept demonstration of "first complete PROTAC"Contact Us then"Low imitation of VHL binding site of HIF1α peptideFinding "The door to the rational design of PROTAC, which is completely low-structural, opened.Facts。

And in 2015, the method of using Futarimide is reported. Winter"BET Bromo domain’s competing antagonist added to the Futarui part and got on the Celebron E3 ubiquitinase complex."HOME Compound dBET1"In vitro and in vivo highly selective protein decomposition"Facts。

3 Ways (Concept diagram) Left = conventional in tor / middle = PROTAC (designed) / right = adhesive (punched on the surface) Traditional low- in tors PROTAC Adhesive Target active parts E3 Ligerze E3 Ligerze Stop the active part by blocking One-to-one relationship with targets "Effective with quantitative (Occupancy Drive)"," ated parts Protein remains Target join + linker + E3-bonded 33 parts Select an array and design ration No active parts needed Dissolved by protein Not functional Like a wedge on the surface Improve interaction s can be small Dissolved by protein The same "decomposition" result is realized by completely different 、 design. * The ratio of 3 depends on the description of Békés et al (2022) [Reference Material 1]. * The rectangle is a block that indicates the role and does not indicate the orientation of the shape, size, and binding of protein.
Fig. 2 Concept diagram (vector drawing).The ratio of 3 depends on the description of Békés et al (2022) [Reference Material 1].The rectangle is a block that indicates the role, and does not indicate the direction of the three-dimensional structure and binding of protein.This article organizes three columns.

4. Differences from low- in tors - from occupancy to events

Paper description: why "not targeted" changes to "not yet targeted"

Békés et al. organizes the premise of conventional drug discovery. "“To date, traditional low-affinity drug discovery research on targets in cells has been focused on the development of high-affinity targets targeting the active or sterical sites of proteins. This was a very effective method, but as a result, the potential drug target remains undetected or insufficient drug discovery.”Facts

and"PROTAC targets decomposition function (the pharmacology of event-driven), thus eliminating the need for the active site and simply redefining "thing that is not yet targeted"Facts。

The same theory is the target condition for PROTAC「PROTAC target」HomeFacts。

Paper Description
There is a deviation from the natural state"Excessive expression, mutations, agglomeration, isoform expression, and localization are removed from the natural state, resulting in function acquisition that causes the disease."
E3 ligase has a near surface"E3 ligase bindable surface"Yes. It is essential that the ligase arrives near the ligand binding site
There is a part that passes through the protector somIdeally"Non-structured area for passing through proteasom"Yes
ed affinity is good at mediumHowever,"Medium-hyaluronic acid affinity (1~500)M or more) is usually necessary"Made
Targeted targeted with resistant mutations"“Protein that has gained resistance mutations to targeted treatment, protein with scaffold function, and protein that is considered to be ‘not targeted’ in other modalities can also be very suitable as PROTAC’s target.”
Cell surface protein is not suitable"Cell surface protein is not considered optimally now"

AllFacts(Békés et al 2022 [Reference 1]). The theory of resistance mutations,“With the pharmacology of event-driven (not occupancy-driven), PROTAC can overcome the insensitivity to such resistant mutations through the catal、 decomposition of the target.”Facts。

However, it is not possible to combine strongly.

Békés et al al stipulates the points to be cautious about the three-dimensional illusion (rigase-PROTAC).

"The formation of the three-dimensional illusion is necessary for the action of the PROTAC。, but the degree of the three-dimensional illusion can differ depending on the substrate. That is, the three-dimensional illusion that forms less efficiently and remains solidly coupled does not lead to efficient decomposition.Facts

MoreThe cooperativity, which indicates the degree of three-dimensional illusion formation in hetero two functions, can be positively negative by combination of ligase and targetContact UsFacts。

Occupational drive and event drive (conception diagram) "Top = In-tors are tied one-on-one with the target, and the effect is determined at the occupancy rate / lower = decomposition in-tors are removed and rotated next Occupancy drive (conven in tor) 1 drug + 1 target 1 drug + 1 target 1 drug + 1 target ... only a number of targets are required If the drug is removed, the target function is back. The target protein itself remains in the cells Event drive (decomposition derivative) Decomposition of 1 piece 2 pieces 3 pieces "...Co-operations turning the same 1-to-1" Target protein disappears. To return the effect, cells need to add new protein content However, when the three-dimensional illusion remains firmly combined, the decomposition will not proceed efficiently * The description of occupancy drive and event drive ratio, recycling and three-dimensional illusion depends on Békés et al (2022) [Reference Material 1]. * Figures are imitations of the way of thinking, and do not indicate the actual rotation speed or decomposition speed.
Figure 3 Concept diagram (vector drawing).The description of occupancy drive and event drive ratio, recycling and three-dimensional illusion depends on Békés et al (2022) [Reference Material 1].The figure is an expression of the idea, and does not indicate the actual number of revolutions, decomposition speeds, and the number of。s.

5. Perspective of material ians 1: This is a catal rather than a drug

Material ians read: Design indicators move from affinity to rotational efficiency

Let's replace the quotes to this article with the words of the catal。.

  • Substrate:Target protein
  • Catalyst:Decomposition in a Gateway (+E3 ligase)
  • :Three-dimensional illusion (ligase-decomposition derivatives-target)
  • rate:Ubikitinized target = sent to Proteasome
  • Catalyst Regeneration:PROTAC will recycle and target the following POIs.Facts

This replacement is effectiveThe optimal point of design is not “st ”Comment“The three-dimensional illusion that is formed very efficiently and hardly combined does not lead to efficient decomposition.”CommentFactsHome It is exactly the same as familiar composition with uneven catal's (This article explains). If the absorption is too weak, the reaction does not stop, and if the product is too strong, the catalyst does not rotate without leaving the product. al value is in the middle.

So binding affinity demands, too"Medium-hyaluronic acid affinity (1~500)M or more) is usually necessary"It is a wide expressionFactsHome If you are an in tor, it is written as "I want to raise up to the picker" (in this article).

Another thing is that the material engineers can read. The time until the effect returns is determined by the speed that cells make protein rather than the degradation timeIt is. In tors return water if the drug disappears, but decom targetsDoes not return until re ed(This article) ——This changes the design concept of the drug dysfunction itself.

6. E3 ligase – There are more than 600 types, but two are mainly used

The design of the decomposition inductor leaves the best choiceWhich E3 ligase to useComment

Paper Description

Békés"There are more than 600 types of human E3 ligases that can be explored"What is actually used?CRBN and VHLis centered, "CRBN and VHL, the original "worker" of target protein decomposition, are enough to replace them."Facts。

The selection of ligase is also expressed to change the results. The difference in the decomposition profile given by different ligases can be driven by several factors. One is ligase and target shape compatibility. The second is the ability to form a degradable three-dimensional illusion between ligase and POI.”Facts

Examples of CRL4–CRBN, CRL2–VHL, CRL1–β-TRCP, CHIP, etc. “These collectives show the difference between the size, shape, and electrostatic potential surfaces of each ligase, which can affect the decomposition of various targets.”Facts。

The reading of the material ian: "the same function parts have 600 kinds of shelves"

This situation makes it easier to understand if you replace it with the words of material selection. There are more than 600 types of Ubi parts, There are differences between shape and surface charge. There are two types of products.

Why two types?"Less ligands are found". In order to use E3 ligase, low-affinity are required to bind to that ligase. For CRBN, low-affinity imitation of HIF1α peptide was known for salidomide affinity and VHL.Facts。 In other words, this is a “restriction on inventory” rather than “elimination of performance”(This article)

And if this design is canceled, the freedom of design spreads at once. Comment“In search of more than 600 human E3 ligases, the question is ‘when’ and ‘for any disease’ rather than whether the target protein decomposition treatment on the new E3 ligase arrives to patients.”I wroteFacts。 This is a、, not a track recordUndetermined / Future。

7. Calculation in this paper: Where does the weight swell?

To grab two proteins simultaneously,Contains two ligands and linkers into onerequired. The price is the amount of 。.

Numbers that will be the starting point (both the listed values of the published materials)
  • rule of 5：Lipinski"In the search phase, "rule of 5" predicts that the absorption or transmission is likely to be faulty when the hydrogen bonding body is more than 5, the receptor is more than 10, the MW weight (MWT) is more than 500, and the calculation Log P (CLogP) is more than 5 (or MlogP > 4.15)."Facts
  • Topdeggerant (PROTAC, oral):Formula C45H49N5O4、weight 723.90Facts
  • Lenalidomide (Mole) Adhesive, Oral):Formula C13H13N3O3、weight 259.3Facts
  • Iberdinate hydrochloride (Celebrone-adjusted decomposition derivative, oral):Formula C25H27N3O5・HCl、weight 485.97Facts
Calculation: Excess and Part-by-Part

Convert from aboveThe calculation of this paper。

  • rule of 5723.90 ÷ 500 ＝ Approx. 1.45 timesHome Excessabout 224
  • E3 process:723.90 − 259.3 ＝ about465。Already a weight of one low drug with only the remaining "target binding part + linker"
  • Iberd gum (equivalent to free base except hydrochloride):485.97 − 36.46（HCl）＝ about449.5。rule of 5
  • 2 dosage ratio:723.90 ÷ 485.97 ＝ Approx. 1.49 times。Even with the same "degradable medicine", the weight is 1.5 times different depending on the mold

Premises and Limits:"E3 binding part occupies"Calculation of lenalidomide's weightComment The E3 binding part of Topdejestrant is not the value of Renarido. However, compared to the chemical name of both parties,Partial structure of the same surface including "isoindole-2-yl" and "piperidin-2,6-dion"can be readFacts(The comparison of the structure is explained in this article. It does not mean the problem of quality or safety by itself that the molecular weight is large.)

Comparison of weight (different from weight) Attachments and Lipinski et al. rule of 5 500 Leonardo 259.3 Iberdo Hydrochloride 485.97 723.90 rule of 5 ulation: 723.90 ÷ 500 = about 1.45 times. 723.90 − 259.3 = approx. 465 (target binding section + linker guide) In the same "degradable medicine", the weight of PROTAC and adhesive is about 1.5 times different. ※ 500 is based on the description of Lipinski et al (2001) [Reference Material 7] and each 。 weight is attached [Reference Material 8 · 9 · 10]. * 1.45x, 465x, and 1.49x are calculated in this article. Approximately 465 is an approximate calculation of the molecular weight of lenalidomide.
Figure 4 Drawing including calculation of this paper (vector drawing).The approximation of 500 is Lipinski et al (2001) [Reference Material 7], and the 。 weight depends on each attachment [Reference Material 8, 9, 10].1.45x, 465x, and 1.49x are calculated by this article.* 465 is an approximate calculation of the molecular weight of the E3 bonding system in the lenalidomide method.

8. Oral Absorption Wall – approved two-agent attachments

2026,FDATwo types of decomposition in agentsapproves the following. VEPPANU, Hetero Dual Function = PROTAC Iberdo Fellow (ZENBEXUS) on August 13"Celebrone-adjusted protein decomposition derivative"HomeFacts。 Both oral agentsAttachments are written in the same format. When aligned, the difference in the size of the is expressed as the number.

VEPPANUZENBEXUS
TypeHetero2 FunctionalityHome Linked ER-bound domain and E3-ligase-bound domain with linkerCoupling to Celebr, calling Aiolos Ikaros and beteting and decompositioning
Weight723.90485.97(hydrochloride)
ChemicalsFilm coating tablets 100 mg/200 mgHPMC Capsules mg/1 mg
SolubilitypH dependency。"Easy soluble in stomach pH conditions, slightly soluble in intestinal pH conditions"(This document is not within the scope confirmed)
Effects of dietHigh Fat FoodAUC 2.9x, Cmax 3.2xHome UsageMeal“Even if given with meals, there is no clinically meaningful difference.”
Effect of gastric acid in torEsomeprazoleAUC 84%, Cmax 74%Dropped to(This document is not within the scope confirmed)
Plasma Protein BindingOver 99%75%
Distribution volume of view764 L415 L
TmaxAbout 6 hours2 hours
Half-Life19 hours37 hours
about 68%(unchanged body 18、, in urine 1.5%(under 0.02%)In Urine about 46%(Unchanged body 16、, segment about 43% (unchanged body 11、

AllFacts(VEPPANU attachment [Reference Material 8], ZENBEXUS attachment [Reference Material 9])2Drugs are different from target and target disease, so this table is intended to see the trend of physical and drug efficacy and does not compare efficacy and safety.

Calculation: Multiple numbers

Convert from table valueThe calculation of this paper。

  • Free type (not binding to protein):Top 100% - 99% super = Less than 1%Iberd Japan Co., Ltd. 25%。25 times or moreHome
  • Urine retion:46% ÷ 1.5% ＝ Approx. 31 timesHome Top 100%Don’t go through the kidneys
  • Number of mors per time:200 mg ÷ 723.90 g/mol ＝ Approx. 0.28 mmol1 mg ÷ approx. 449.5 g/min about 0.0022 mmol。Approx. 120 timesAperture
  • Weight:200 mg ÷ 1 mg ＝ 200 times

Premises and Limits:Since "99% super" is the lower limit, it can only be said to be "less than 1%". 2Drugs are completely different from the basis of target, target disease and dose setting,Large and small doses do not mean the strongness of the effectHome These magnificationsHow the properties of s come to formulationto see.

The number of attachments can be displayed side by side (including calculation of this document) Left: Beppede Gestrant (Mole Weight 723.90) / Right: Iberd (485.97) with hydrochloride 2.9 times AUC in high-fat diet (Left agent) Influ is 'clinically meaningless difference' 25 times or more Free type opening Less than 1% vs 25% (cal ating this article) Approx. 31 times Opening of urine retion 1.5% vs. 46% On the side with large weight, the following properties are assembled Solubility depends on pH (easy to soluble in the stomach, slightly hard to melt in the intestine) Absorption volume changes greatly in the diet / absorption amount decreases when suppressing gastric acid Almost all of the plasma proteins are combined and reted to almost any manure Each is a typical line indicating that there is a stage in the stage of 'melt and absorbed' (Commentary by this article) * Each number is based on VEPPANU attachment [Reference Material 8] and ZENBEXUS attachment [Reference Material 9]. 25 times or more, about 31 times is the value calculated by this article. ※ 2Drugs differ from target disease. It is not a comparison of efficacy and safety.
Figure 5 Drawing including calculation of this paper (vector drawing).Each number depends on the value of VEPPANU attachment [Reference Material 8] and ZENBEXUS attachment [Reference Material 9]."25 times or more" and "31 times" are calculated by this article, not publicly available.This article explains the reading below. 2It does not compare the effectiveness and safety of the agent.

9. Perspective of material ians 2: Filling the insufficient solubility with preparation

In a transparent water, a collection of fine grains of light colors spreads slowly, and an abstract concept image that swells
Figure 6 Concept diagram (AI generation image).It expresses the idea of "the melting and spreading stage becomes the entrance of absorption".It does not show the actual formulation, tablets, and e tests.
Material ians: Additives can be found in the list.

VEPPANU attachment contains active ingredientsInertis enumeratedFacts。

  • Tablet contents:Colloidal silicon dioxide, crosscarmellose sodium, hypromellose, lactose hydrate, crystal cellulose, phthalate sodium, phthalateVitamin E - Polyglycol Coate Ester
  • Film Coating:Polyvinyl alcohol,Polyvinyl Alcohol - Poly Glycol Grapht CopolymerGlycerin Mono/Dicaprilocapurate ester, talc, titanium oxide, pigment (indigocarmine aluminum rake, yellow and black iron oxide)

Here's how to draw eyesVitamin E - Polyglycol Coate Ester(This article explains). Name:Fat-soluble vitamin E (tocopherol) and water-soluble poly l part are connected with co-enzyme AIt is a parent of the parent's medium. On the other hand, the inside of the capsule of the Iberdo capacitor weighs about 486Anhydrous Lactose, Alfaー starch, Stearic acidonlyFacts。 The molecule is large, and the solubility depends on pH, and only the preparation of the side where the absorption changes three times in the diet is included in the additive of the parent's medium.Dutch This contrast can be read as a composition in which the formulation compensates for lack of physical properties (in this article).

The attachment does not describe the purpose of this additive. Therefore, it can not be determined that "entered for soluble"(This article) But the facts in the attachment—AUC is 2.9 times higher in high-fat foods that are easy to dissolve in the stomach and intestines, and AUC is 84% with gastric acid in torFactsDutch AllConstraints on the stage of melting and absorbingshow.

This is the reason for material engineers.(This article) Decomposition inductors at the stage of designrule of 5Contact UsFactsHome If you do not fill it,Surfactants, Dispersive Stabilizers for Polymers, Copolymers for CoatingsThis is the area where chemical materials are responsible. Békés et al. about oral compounds outside ofle of 5 "Hydrogen-binding body, topological polarity surface area, cLogP"Please note that Short linker to adjust the weight and physical properties of PROTACLinker"Three-dimensional distribution in a solution"to contribute toFacts。 Linker in s and additives in tablets — the same problem is solved in two levelsSorry, this entry is only available in Japanese.

10. Development and approval status (reco zed by regulatory officials)

The following:FDA’s Drugs@FDA has the date of initial approval (ORIG-1) and has confirmed the mechanism of decomposition induction by attachment or review theoryComment It does not treat inferior or clinical results of efficacy and effect.

Product nameTypeFirst Approval (FDA)Description of the order and approval category
THALOMID
(Salidomide)		adhesives (after-determined)July 16, 1998
（NDA 020785）		Békés et al is the mechanism of action of saridomideUnraveled after FDA approvalContact Us Ito et al (2010)
REVLIMID
(Lenalidom)		adhesives (after-determined)December 27, 2005
（NDA 021880）		AttachmentsAiolos, Ikaros, and CK1α are targeted for biotinylation and decompositionContact Us
POMALYST
(Pomarido))		adhesives (after-determined)February 8, 2013
（NDA 204026）		Békés et al said that Saridomide Lenalidomino Pomarido uses CRBN
VEPPANU
(Bepdegerant)		Hetero2 Functionality(PROTAC type)May 1, 2026
NDA 2)5		AttachmentHetero2 Functional Protein Decomposition InductorHome Join ER and CRBN.No quick approvalHome ESR1 mutationsFDA approved inspectionto confirm
ZENBEXUS
(Iverd))		Celebrone-adjusted decomposition inductorsAugust 13, 2026
NDA 221075		Attachment"Celebrone-adjusted protein decomposition derivative"。Quick approval(Based on the complete response of minor residual lesions),The clinical validation in the verification test can be a condition of continuous approvalContact Us Use with daunomab hyaluronidase compounds and dexamethasone

FDA Drugs@FDA [Reference Materials 11], FDA Drugs and approval classifications are included in each attachment [Reference Materials 8・9・10], and Saridomides are positioned by Békés et al (2022) [Reference Materials 1] and Ito et al (2010) [Reference Materials 4].Facts。The approval of Bepped Gestrant and Iberdo Fellows in Japan (PMDA) was not confirmed at the time of the investigation (September 2026).Undetermined / Future。

Clinical Trials (ClinicalTrials.gov)

NCT NumberTarget decomposition in the deviceNumber of phases/registrations/s ations (inlin with ClinicalTrials.gov)
NCT03888612A)-110Phase 1/2, 248, Completed (COMPLETED)
NCT04072952A)-471Phase 1/2, Registration 217, Completion (COMPLETED)
NCT05654623VERITAC-23rd phase, 624 cases, ACTIVE NOT RECRUITING

AllFacts(ClinicalTrials.gov) ARV-110 and ARV-471"PROTAC first given to humans"HomeThe first clinical concept demonstration of ER and AR established cancer target in 2020Contact UsFactsHome VEPPANU Attachments VERITAC-2Uns・rated, Non-Blinded, Anti-Pharm Control270 cases with ESR1 mutations)Facts。This article does not handle test results.

This article
  • Disassembly inductors can be placed on the cell disposal line instead of blocking the target.E1, E2 and E3 bring E3 ligase to the targetFacts
  • PROTAC designs and assembles three parts, and the 。 adhesive enters the interface like a wedge.I found that salicylamides are adhesives laterFacts
  • The action is catal .However, if the three-dimensional illusion is too tightly combined, the decomposition is not progressed, and the optimum point is in the middleFacts
  • There are more than 600 types of E3 ligase, but CRBN and VHL are mainly used.Facts
  • PRO weight of PROTAC type oral agent approved in 2026 is 723.90, about 1.45 times the rule of 5The calculation of this paper
  • On the big side of the weight, pH-dependent solubility, influence of large meals, and over 99% protein bonds are together.Its tablets contain additives of parent-borneFacts

11. Glossary

Target protein decomposition (TPD)
The concept of treatment that does not in t target protein and dissolves into cells.
PROTAC
Decomposition in the device of heterogeneous function consisting of target binding, linker and E3 binding.
Adhesive
Decomposition induction agent that enters the E3 ligase and targeted surface and strengthens interaction.
"Tags" of small proteins attached to decompose proteins.
pro
A cell decomposition device that cuts protein with biotin tags.
E1・E2・E3
Three-stage s that contribute to the activation, transport, and substrate of biotin.
E3 Ligerze
Enzyme determining which protein you want to tag. More than 600 types of humans
CRBN
The component of the E3 ligase complex that the salidomide joins.
VHL
Phon Hippel-Lindow tumor suppressor. E3 commonly used in PROTAC.
body
E3 ligase, PROTAC decomposition, and target state combined simultaneously.
Contact
Stronger or weaker than expected from single binding.
Fortune Drive / Event Drive
The pharmacology that works only while binding and decomposition.
rule of 5
In the case of 500 weight 500 or more, it is a rule of experience that absorption is prone to becoming inferior.
Free Type
Add drugs that are not combined with plasma proteins.
AUC
Blood concentration - time curved lower area. Total amount of drugs in the body.
Quick approval
FDA System. Approve in an alternative evaluation item and ask for verification in the verification test.

12. Reference materials (primary information)

  1. Békés, M., Langley, D.R., Crews, C.M.「PROTAC targeted protein degraders: the past is prologue」Nature Reviews Drug Discovery 21(3), 181–200 (2022). doi:10.1038/s41573-021-00371-6 — pmc.ncbi.nlm.nih.gov
  2. The Royal Swedish Academy of Sciences"The Nobel Prize in 2004 — Press release" October 6, 2004 — nobelprize.org
  3. Sakamoto「Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation」PNAS 98(15), 8554–8559 (2001). doi:10.1073/pnas.141230798 — pmc.ncbi.nlm.nih.gov
  4. Ito, T. etc.「Identification of a primary target of thalidomide teratogenicity」Science 327(5971), 1345–1350 (2010). doi:10.1126/science.1177319 — pubmed.ncbi.nlm.nih.gov
  5. Krönke, J. etc.「Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells」Science 343(6168), 301–305 (2014). doi:10.1126/science.1244851 — pmc.ncbi.nlm.nih.gov
  6. Winter, G.E.「Phthalimide conjugation as a strategy for in vivo target protein degradation」Science 348(6241), 1376–1381 (2015). doi:10.1126/science.aab1433 — pmc.ncbi.nlm.nih.gov
  7. Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J.「Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings」Advanced Drug Delivery Reviews 46(1–3), 3–26 (2001). doi:10.1016/S0169-409X(00)00129-0 — pubmed.ncbi.nlm.nih.gov
  8. FDA"VEPPANU (vepdegestrant) Tablet Attachment" NDA 2 5, 2026 (PDF) — accessdata.fda.gov
  9. FDA"ZENBEXUS (iberdomide) capsules" NDA 221075, August 2026 (PDF) — accessdata.fda.gov
  10. DailyMed（U.S. National Library of Medicine）"REVLIMID (lenalidomide) capsules" — dailymed.nlm.nih.gov
  11. FDADrugs@FDA: FDA-Approved Drugs — accessdata.fda.gov
  12. ClinicalTrials.gov「NCT05654623（VERITAC-2）」 — clinicaltrials.gov
  13. ClinicalTrials.govNCT04072952 (ARV-471 Phase 1/2) — clinicaltrials.gov
  14. ClinicalTrials.govNCT03888612 (ARV-110 Phase 1/2) — clinicaltrials.gov

13. Response Table of Claim and Source (Audit)

ContentHome
Definition of TPD. One end of PROTAC is POI, the other ends are combined with E3 ligase, and then recycled after decomposition by POI ligization and UPS. The mechanism of action and event-driven pharmacology of catalysis are distinguished from classical in tors that are driven by chemical instruments that have a single-to-one relationship with POI. Based on the discovery of salicylate adhesives of salidomides, the ligase and substrate PPIs are not functional, and the mechanism of action of salidomide is identified after FDA approval. In 2001, PROTAC-1 is the first complete peptide PROTAC in vitro concept demonstration, the low-body imitation of the VHL binding site of HIF1α peptide opens the door to the fully low-body PROTAC design, and the use of CRBN. To red the ratio between occupancy drive and event drive, "not targeted" as "not yet targeted". PROTAC-targeted tuna (deviations from natural state, surfaces where E3 can be sintered, non-structured areas, neutral affinity 1-500MM or more, to resistant mutations and sintered proteins, not optimal for cell surface proteins), to overcome non-sensitivity to resistant mutations. It is necessary for the three-dimensional illusion, but if it is too hard to join, it will not cause efficient decomposition, and cooperation will be negative. The difference between CRBN and VHL may be replaced by the original worker, the difference in the disassembly profile by the ligase is due to the morphophysiological function, the size, shape, and electrostatic potential of each ligase are different, and the new E3 ligase use will be questioned when and which disease. The rule of 5 is made as a guideline for HTS library construction in the 1990s. The PROTAC has two functions, so it is noted that it is out of it, it is possible to adjust the weight and physical properties with a short linker, and the linker contributes to the solidarity in the solution. ATAC-110 and ARV-471 were first administered to humans, and in 2020, the first clinical demonstration of ER and AR was obtained.Békés et al (2022)[Reference 1]https://pmc.ncbi.nlm.nih.gov/articles/PMC8765495/Facts
The Nobel Chemical Award in 2004 was awarded to Chicanoer, Harshko and Rose for the discovery of protein decomposition through Bektin, and the date of the presentation is October 6, 2004. The decomposition is finely controlled and the proteins to be decomposed are tagged with a protein and fragmented with a Bektin. The tag is Bektin and is recycled just before being pushed into the protector som.Nobel Prize 2004 Press Release[Reference 2]https://www.nobelprize.org/prizes/chemistry/2004/press-release/Facts
Protac-1 is composed of two domains of IκBα phosphate and ovalcin, which are recognized as β-TRCP, and MetaAP-2 is linked to SCF (β-TRCP), and Protac-1-dependent Bektinization and decomposition.Sakamoto et al (2001)[Reference 3]https://pmc.ncbi.nlm.nih.gov/articles/PMC37474/Facts
Celebrone (CRBN) is identified as a salidomide binding protein and forms an E3 Bektin ligase complex with DDB1 and Cul4A.Ito et al (2010)[Reference 4]https://pubmed.ncbi.nlm.nih.gov/20223979/Facts
Quantitative proteomics revealed the mechanism of selective decomposition of the E3 Bektin ligase activity by lenalidomide, which found that IKZF1 and IKZF3 CRBN-CRL4 causes selective Bektinization and decomposition.Krönke et al)[Reference 5]https://pmc.ncbi.nlm.nih.gov/articles/PMC4077049/Facts
BET Bromo Domain’s Competent Antagonist has been added to the Futarit part to take the CRBN E3 Bektin ligase complex, dBET1 in highly selective CRBN-dependent BET protein decomposition in vitro and in vivo.Winter 2015[Reference Material 6]https://pmc.ncbi.nlm.nih.gov/articles/PMC4937790/Facts
Predicting that the rule of 5 is likely to be poorly absorbed or transmitted when the hydrogen bonding body exceeds 5, 10 or more receptors, 500 or more weight, CLogP 5 or more (or MlogP 4.15 or more)Lipinski et al (2001)[Reference Material 7]https://pubmed.ncbi.nlm.nih.gov/11259830/Facts
ER-binding domain and E3-ligase-binding domain are low domains with linkers, ER-binding and CRBN-binding polyketinization and proteasome decomposition by CRBN, including 2,6-piperidine dione and isoineryl-2-yl, ER formula C45H49N5O4, 2.9 weight 723.90, dissolved in the stomach volume with pH, half-life, and octocoric acid, non-contaminated polymeric acid, 12%, 12% ESR1 mutations are checked by the FDA, and the validity was evaluated by VERITAC-2 (unsuccessful, non-approved, drug contrast, 270 ESR1 mutations among 624 cases).FDA VEPPANU[Reference 8]https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/219835Orig1s000lbl.pdfFacts
Iberdo hyaluronic acid binds to CRBN through the "CRBN-adjusted protein decomposition agent", the call of Aiolos Ikaros, Bektinization and proteasome decomposition, the 485 formula of hydrochloride C25H27N3O5・HCl・Molecular weight 485.97, 485 mg・1 mg HPMC capsules, which are not expected to be a clinically meaningful difference in diet, tampak binding hyal, Vsmogenesis, 23%, 23% of urine, 23% of hyalone, 23% of hyaluronic acid and 21% of hyaluronic acid.FDA ZENBEXUS[Reference 9]https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/221075Orig1s000lbl.pdfFacts
Aiolos, Ikaros, and CK1α are targeted for Bektinization and decomposition through the cell-level activity of lenalidomide (constituent elements of the Bektin ring E3 Bektin ligase complex). The chemical name is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl) piperidine, molecular formula C13H13N3O3, molecular weight 259.3DailyMed REVLIMID[Reference Materials 10]https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296beFacts
FDA approval date and examination classification (THALOMID July 16, 1998 / NDA 020785, REVLIMID December 27, 2005 / NDA 021880, P LYST February 8, 2013 / NDA 204026, VEPPANU May 1, 2026 / NDA 2165 · Standard examination, ZENBEXUS August 13, 2026 / NDA 221075 · Priority examination · Rare disease)FDA Drugs[Reference Materials 11]https://www.accessdata.fda.gov/scripts/cder/daf/index.cfmFacts
NCT05654623 has been registered for 624 cases in Phase 3 trials of Beppede Gestrant and has been closed.ClinicalTrials.gov[Reference Material 12]https://clinicaltrials.gov/study/NCT05654623Facts
NCT04072952 is complete with a single agent of ARV-471 and the 1/2-phase trial of palbocyclib.ClinicalTrials.gov[Reference 13]https://clinicaltrials.gov/study/NCT04072952Facts
NCT03888612 is complete with 248 instances of ARV-110ClinicalTrials.gov[Reference 14]https://clinicaltrials.gov/study/NCT03888612Facts
723.90 ÷ 500 = about 1.45 times (excess 224), 723.90 - 259.3 = about 465, 485.97 - 36.46 = about 449.5, 723.90 ÷ 485.97 = about 1.49 times. The free mold is less than 1% and more than 25 times, about 31 times the urine retion, about 0.28 mmol and about 120 times the number of mors per time, and 200 times the mass.The article discusses the calculation of this paper. It is assumed that this article replaces the weight of the E3 bonding system with lenalidomide, deducting the weight of HCl. The magnification is to observe the trend of physical and drug biology, not to compare the efficacy, safety, and dosage validity of the two drugs.The calculation of this paper
Approve of beep degeneratives and ibardents in Japan (PMDA) and practical use of decomposition derivatives that use new ligases out of 600+ E3 ligasesThe primary information indicating approval and utility was not confirmed at the time of the investigation of this article (September 2026). Békés et al.Undetermined / Future
Vitamin E - The purpose of adding poly l-lactate esters is to determine the manufacturing process, production cost, and original medicine for each product.There is no description of the purpose in the attached document, and it is not stated because the primary information published in the scope of the investigation of this article cannot be confirmed.
Inferior efficacy and effect of each product, evaluation of clinical results, safety, recommendation of usage and dosageThis article explains chemical, material, and preparation technology and does not evaluate the effects and safety of the treatment. The usage (including meals) is quoted in the attachment to determine the dosage of the preparation.
The decomposition induction agent is a catalyst, and the optimal point of the three-dimensional illusion is the optimal value of the catalytic absorption strength of the uneven catalytic surface. Read that the effect depends on the reactivity of protein. E3Rigase is "inventory". Read that the properties of dissolving and absorbing are demonstrated on large weights. I read the existence of my parents' additives as a composition to compensate for the lack of physical properties, and I organized a linker and additive to solve the same problem in two hierarchies. I read the same part structure from the chemical name of the agent.Also commentary of this article based on the publication content. It is not the opinion of authors, regulators and companies of each paper.
Fig. 1 - Fig. 5 is a drawing for explanation, not the actual structure and three-dimensional structure of the protein. The hero image and Fig. 6 must be an AI-generated image.Notes by this article

Last Updated: September 26, 2026/Source is limited to primary information (FDA-approved documentation and Drugs@FDA, ClinicalTrials.gov, Nobel Foundation announcements, reader review papers). They are distinguished from the facts as "explanation" because they include readings in chemical design and formulation design. The purpose of adding additives, the manufacturing process, the production cost, and the approval status in Japan are not listed because it is not possible to confirm with the primary information published. 2 Comparison of the drug content of the drug is to see the trend of physical properties,It is not a comparison of efficacy and safety. This article is an explanation of chemical, material and preparation technology.It does not evaluate the effectiveness and safety of the treatment, but it is not medical advice. [Translation 2] All diagrams are illustrations for explanation. Fig. 1 to Fig. 5 is a vector drawing, and Fig. 6 is an AI-generated image.We do not show actual s, proteins and products.

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