Make it an alternative and advantageous approach to genetic knockdowns The acute, profound, and reversible effect of this class of compounds
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Provide useful chemical tools for posttranslational protein knockdown. 19 In addition to their therapeutic potential, BET-targeting PROTACs Therapeutic profiles over BET inhibitors. 30 BET-targeting PROTACs could provide advantageous (MLL) 28, 29 as well as NUT-midline carcinomas. Including acute myeloid leukemia (AML) and mixed lineage leukemia Scaffolds, 26, 27 that are in >20 clinical trialsĪgainst a variety of diseases, mainly solid and hematological cancers 16, 19, 21, 22 BET proteins are particularlyĪttractive targets, with a dozen of BET inhibitors from different Reported potent activities and specificity in cells and in vivo ofīoth VHL-based 5, 16− 20 and CRBN-based 18, 20− 25 PROTACs against several targets, including the bromodomain and extra-terminal As a result of these developments, we and others recently
VECTOR TD LEVEL 50 FULL
(VHL, e.g., 1 (VH032), Chart 1) 9− 11 and cereblon (CRBN, e.g., 2 (pomalidomide), Chart 1) 12− 15 greatly contributed to full realization of the technology’s Small molecules for the Cullin RING E3 ubiquitin ligases (CRLs), 8 in particular against von Hippel–Lindau Of the early generation compounds that typically incorporated peptidicīinders for E3 ligases. Over the following decade were in large part hampered by poor druglikeness 4, 5 First introduced by Crews and Deshaies in 2001 (ref ( 6)), developments of the technology Ligase conjugated to a ligand binding the target protein. (also known as PROTACs) which comprise a ligand binding an E3 ubiquitin 1− 3 One approach to induce protein degradation is toĭesign heterobifunctional molecules called proteolysis-targeting chimeras System has recently emerged as a new modality of intervention for
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Relationships of bivalent degraders are anticipated to have wide future The provided insights and framework for structure–activity Generate more potent PROTACs and underscores the key roles playedīy the conjugation. This work exemplifiesĪs a cautionary tale how a more potent inhibitor does not necessarily Linker length was observed for BET-degrading and cMyc-driven antiproliferativeĪctivities in acute myeloid leukemia cell lines. Which showed negative cooperativities instead. PROTACs exhibited positive cooperativities of ternary complex formationĪnd were more potent degraders than tetrahydroquinoline compounds, Polyethylene glycol linkers to VHL ligand VH032. Tetrahydroquinoline I-BET726, via distinct exit vectors, using different Here we examined the impact of derivatizing two differentīET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent PROTACsĬonjugate a target warhead to an E3 ubiquitin ligase ligand via a Small-molecule approach for inducing protein degradation. Design of proteolysis-targeting chimeras (PROTACs) is a powerful