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The Carna Biosciences CDC7 kinase inhibitor, AS-0141, is a clinical candidate for cancer with a structure that contains a hydrazine, furenone, and ester, all rare functional groups for an oral molecule. The molecule has a long residence time on the kinase, and despite a short half-life in mouse, extended target engagement is observed >24 h post-dose.…

Bristol Myers Squibb (BMS) oral JH2-domain binding Tyk2 kinase inhibitor

The academic covalent ALKi inhibitor, Con B-1, is thought-provoking initial proof-of-concept that remote kinase cysteines might be targetable from an active-site inhibitor. The authors show that a derivative of ceritinib with a remote electrophile attached can inhibit ceritinib more potently than a non-reactive control compound, that linker length significantly impacts activity, and that a 1:1…

The JNJ AR antagonist, JNJ-63576253, is a clinical molecule for prostate cancer that is active against both wild-type androgen receptor as well as the clinically relevant AR mutant, F877L. F887L is a devious resistance mechanism that transforms antagonists of AR into agonists. The parent compound from which 6253 is derived was found to be unacceptably…

8. The EicOsis oral soluble epoxide hydrolase (sEH) inhibitor, EC5026, is a compound currently intended as a non-opioid analgesic and anti-inflammatory agent. It recently completed a Ph. I study in healthy volunteers without drug-related adverse events. Despite its small size, it has picomolar binding activity with the urea acting as an epoxide-opening transition-state mimic. The…

1.The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist (LSN3318839) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. The starting point was identified from a 220k compound cell-based screen in the presence of…