YKL-5-124

**YKL-5-124** is a potent, selective, and covalent small molecule inhibitor of cyclin-dependent kinase 7 (CDK7), targeting the CDK7/MAT1/CycH complex with an IC50 of 9.7 nM and demonstrating over 100-fold selectivity against CDK2 and CDK9, as well as no inhibition of CDK12/13 at tested concentrations.[1][4][7] It covalently binds CDK7 at cysteine 312 (C312), leading to faster inactivation kinetics than THZ1, inducing G1/S cell cycle arrest, inhibition of E2F-driven gene expression, and reduced T-loop phosphorylation of CDK1 and CDK3 without significantly affecting RNA polymerase II C-terminal domain phosphorylation.[1][7][12] Developed from the PAK4 inhibitor scaffold PF-3758309, it shows cytostatic effects rather than cytotoxicity in various cancer cells, with strong preclinical efficacy in multiple myeloma (MM), neuroblastoma, and pancreatic ductal adenocarcinoma (PDAC) models, including tumor regression and synergy with BRD4 or anti-PD-1 inhibitors.[2][3][5][11]