PROTAC|Inhibitors Agonists Modulators Antagonists|HmoBio.com

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Proteolysis targeting chimera (PROTAC) technology, the recruitment of E3 ubiquitin ligases to induce the degradation of a protein target, is rapidly impacting chemical biology, as well as modern drug development.

PROTAC has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches.

PROTAC-induced protein degradation has yielded impressive preliminary efficacy in a limited number of cellular and in vivo systems but its broader utility and application in a clinical setting is yet to be tested.

The flexibility of the approach is also being steadily expanded by the use of new ubiquitin E3 ligases. While most non-peptidic Protacs have used the E3 ligases VHL and cereblon, more recent reports have shown greater use of members of the IAP family of ligases. Mdm2 may also be a suitable ligase but has so far attracted fewer disclosures.

Between the choices of E3 ligase ligand, the target-binding ligand and both the identity and attachment positions of the linker, there are a number of opportunities to design both very good, and very bad, Protacs in much the same way as with traditional small molecule medicinal chemistry.

PROTAC is now poised to answer some of its most critical questions to see if these novel scientific concepts can indeed translate to agents which deliver real clinical benefit and unprecedented medicine opportunities.

References:

1. Zengerle M, et al. ACS Chem Biol. 2015 Aug 21;10(8):1770-7.

2. Bondeson DP, et al. Nat Chem Biol. 2015 Aug;11(8):611-7.

3. Churcher J Med Chem. 2017 Nov 16..

4. Ottis P, et al. ACS Chem Biol. 2017 Oct 20;12(10):2570-2578.

5. Raina K, et al. cancer. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7124-9.

Cat. No.	Product Name	CAS No.	Information
H9628	GSK-215	2743427-26-9	GSK-215 is a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718;GSK-215 showed differentiated in-vitro pharmacology compared to VS-4718.In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect.
H9547	NJH-2-057		NJH-2-057 is an EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-CFTR.
H9434	BSJ-4-116	2519823-34-6	BSJ-4-116 is a highly potent and selective CDK12 degrader (PROTAC) with an IC50 of 6 nM; BSJ-4-116 downregulates DDR genes through a premature termination of transcription, primarily through increasing poly(adenylation). BSJ-4-116 exhibits potent antiproliferative effects, alone and in combination with the poly(ADP-ribose) polymerase inhibitor Olaparib.
H9430	DP-C-4		DP-C-4 is a CRBN-based dual PROTAC for simultaneous degradation of EGFR and PARP.
H9423	MS4322	2375432-47-4	MS4322 is a First-in-Class,potent protein arginine methyltransferase 5 (PRMT5) degraders with IC50 of 18±1 nM, and also the first degrader of any PRMTs, a class of important epigenetic enzymes.
H9419	GMB-805	2489876-41-5	GMB-805 is a novel potent BCR-Abl PROTAC with DC50 of 30 nM, inducing degradation and demonstrating in vivo activity.
H9392	FC 11	2271035-37-9	FC 11 is a highly potent focal adhesion kinase (FAK) PROTAC Degrader with DC50 values are 40 to 370 pM depending on cell line, which is composed of the FAK inhibitor PF 562217 joined by a linker to the cereblon-binding ligand Pomalidomide ; The effects of FC 11 are reversible upon compound wash out. FC 11 also degrades autophosphorylated FAK (pFAKtyr397), displaying near complete degradation after 3 hours at 100 nM in TM3 cells.
H9325	XY028-133	2229974-73-4	XY028-133 (example 14) is a PROTAC-based CDK4/6 degrader with anti-tumor activity.
H9302	ARV-471	2229711-68-4	ARV-471 is an ER-targeting protein degrader for breast cancer, is a hetero-bifunctional molecule that facilitates the interactions between estrogen receptor alpha and an intracellular E3 ligase complex, leading to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome； ARV-471 robustly degrades ER in ER-positive breast cancer cell lines with a half-maximal degradation concentration (DC50) of ~ 1 nM. PROTAC-mediated ER degradation decreases the expression of classically-regulated ER-target genes and inhibits cell proliferationof ER-dependent cell lines (MCF7, T47D).
H9300	ARV-110	2222112-77-6	ARV-110(Bavdegalutamide) is a first-in-class PROTAC that effectively targets the wild type Androgen Receptor (AR) and certain genomic alterations of the AR (amplification, T878A, H875Y, F877L, M895V, but not L702H or AR-V7) for degradation in both enzalutamide sensitive and resistant preclinical models;ARV-110 showed promising anti-tumor activity in heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC).

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