SY-1365 (Mevociclib, SY1365) is a potent, selective, covalent CDK7 inhibitor with Ki of 17.4 nM.
SY-1365 displayed high selectivity against all other CDKs including CDK2,9 and 12 (IC50>2 uM), and 8 of 468 kinases including CDK7 were inhibited >90% in the kinome screen (DiscoverX KINOMEscan) at 1 uM.
SY-1365 dose- and time-dependently inhibited CDK7 substrates including RNAPII CTD phosphorylation at Ser2/5/7 sites and Thr160 of CDK2, caused massive cell death at 100 and 250 nM SY-1365 24 and 48 hours treatment in THP1, HCC70, and RPE-hTERT cell lines.
SY-1365 induced apoptosis in AML and TNBC cell lines but not in immortalized normal cell lines.
SY-1365 showed significant growth inhibition and cell killing in 386 human cell lines representing 26 cancer types in nanomolar range.
SY-1365 demonstrated substantial antitumor effects in multiple AML xenograft models as a single agent.
SY-1365-induced growth inhibition was enhanced in combination with the BCL2 inhibitor venetoclax.
SY-1365 is more potent, selective, and metabolically stable than THZ1.