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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. Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. ACS Chem Biol. 2015 Aug 21;10(8):1770-7.
2. Bondeson DP, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015 Aug;11(8):611-7.
3. Churcher I. Protac-induced Protein Degradation in Drug Discovery: Breaking the Rules-or Just Making New Ones?. J Med Chem. 2017 Nov 16. doi: 10.1021/acs.jmedchem.7b01272.
4. Ottis P, et al. Assessing Different E3 Ligases for Small Molecule Induced Protein Ubiquitination and Degradation. ACS Chem Biol. 2017 Oct 20;12(10):2570-2578.
5. Raina K, et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2016 Jun 28;113(26):7124-9.

 

Cat. No. Product Name CAS No. Information
PC-35282

HDAC6 degrader 9c

2235382-05-3

HDAC6 degrader 9c (dHDAC6 9c) is a bifunctional molecule (dHDAC6) that could selectively degrade HDAC6, by conjugating non-selective HDAC inhibitor to a thalidomide-type E3 ligase ligand; causes degradation of HDAC6 in a dose dependent manner (DC50=34 nM), upregulate the level of acetylated α-tubulin at 1.1 uM; shows the maximal effect of HDAC6 degradation at 80 nM in the MM.1S cell line.

PC-35213

MT-802

2231744-29-7

MT-802 (MT802) is a potent BTK PROTAC that induces degradation of both wild-type and C481S mutant BTK (DC50=9.1 nM); MT-802 recruits BTK to the cereblon E3 ubiquitin ligase complex to trigger BTK ubiquitination and degradation via the proteasome; MT-802 binds fewer off-target kinases than ibrutinib does and retains an equivalent potency (>99% degradation at nanomolar concentrations) against wild-type and C481S BTK, elicits complete BTK knockdown at 250 nM; reduces the pool of active, phosphorylated BTK in cells isolated from CLL patients with the C481S mutation, whereas ibrutinib cannot.

PC-35152

TL13-112

2229037-19-6

TL13-112 is a novel Anaplastic Lymphoma Kinase (ALK)-PROTAC developed through conjugation of LDK378 and the cereblon ligand pomalidomide; also promotes the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

PC-35151

TL13-12

2229037-04-9

TL13-12 is a novel Anaplastic Lymphoma Kinase (ALK)-PROTAC developed through conjugation of TAE684 and the cereblon ligand pomalidomide; also promotes the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).

PC-63529

MS4077

2230077-10-6

MS4077 is a novel PROTAC (degrader) of ALK, potently decreases cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells (DC50=3 nM); induces ALK protein degradation via cereblon and proteasome dependent mechanism, potently inhibits proliferation of SU-DHL-1 cells with IC50 of 46 nM.

PC-63528

MS4078

2229036-62-6

MS4078 is a novel PROTAC (degrader) of ALK, potently decreases cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells (DC50=11 nM); induces ALK protein degradation via cereblon and proteasome dependent mechanism, potently inhibits proliferation of SU-DHL-1 cells with IC50 of 33 nM.

PC-63465

JH-XI-10-02

2209085-22-1

JH-XI-10-02 is a CDK8 PROTAC based on the CDK8 inhibitor JH-VIII-49, induces partial degradation of CDK8 in Jurkat cells with IC50 of 159 nM.

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