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.
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.
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ARV-771 is a potent BET degrader (PROTAC) in cellular models of CRPC; potently degrades BRD2/3/4 in 22Rv1 cells with DC50< 5 nM, equally potent activity in VCaP and LnCaP95 CRPC cell lines, causes depletion of c-MYC with IC50<1 nM; suppresses both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model.
ARV-825 is a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 via the proteasome; shows more significant and longer lasting c-MYC suppression than small molecule inhibitors (JQ1, OTX015); leads to a superior effect on BL cells proliferation suppression.
dBET1 is a proteolysis-targeting chimera (PROTAC) molecule that appendes a competitive antagonist of BET bromodomain (JQ1) to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex; induces highly selective cereblon-dependent BET protein degradation in vitro (EC50=430 nM) and in vivo and delayed leukemia progression in mice.
MZ1 is a PROTAC that tethers JQ1 to a ligand for the E3 ubiquitin ligase VHL, triggers, induces degradation of the BET bromodomain BRD4; induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3.
CCT-367766 (CCT367766) is a novel heterobifunctional PROTAC that binds and degrades the putative transcription factor regulator Pirin in cells.
dBRD9 is a PROTAC that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex; exhibits markedly enhanced potency compared to parental ligands (10-100 fold).
CDK9-PROTAC is a heterobifunctional small molecule PROTAC capable of cereblon mediated proteasomal degradation of CDK9; selectively degrades CDK9 while sparing other CDK family members in HCT116 cells.
A novel SirReal-based PROTAC that induces isotype-selective Sirt2 degradation (IC50=0.25 uM).
GSK699 (GSK-699) is a potent, cell penetrant PCAF/GCN5 PROTAC, induces concentration-dependent degradation of PCAF and GCN5 in THP1 cells; also potently induces robust and concentration-dependent degradation of PCAF and GCN5 in both macrophages and monocyte-derived dendritic cells (DCs), potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells.
GSK983 (GSK-983) is a potent, cell penetrant PCAF/GCN5 PROTAC, induces concentration-dependent degradation of PCAF and GCN5 in THP1 cells with DC50 value of 1.5 nM and 3 nM, respectively; also potently induces robust and concentration-dependent degradation of PCAF and GCN5 in both macrophages and monocyte-derived dendritic cells (DCs), potently modulate the expression of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells.
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