YX0798 is a potent, selective and oral bioavailable CDK9 inhibitor with binding Kd of 0.28 nM, 16-50-fold more selective for CDK9 than CDK7, CDK3, or CDK4.
YX0798 binds to CDK9 in the ATP binding site.
YX0798 has a greater CDK9 affinity and selectivity than AZD4573.
YX0798 (IC50 = 25.2-109.9 nM) is highly potent in killing BTKi-sensitive MCL cells (Mino and JeKo 1) and BTKi-resistant cells (JeKo BTK KD and Z138), but not healthy PBMCs.
YX0798 potently inhibited cell viability and induced apoptosis in all MCL cell lines tested.
YX0798 inhibited CDK9 phosphorylation, induced poly-ADP ribose polymerase (PARP) and caspase 3 cleavage, and reduced anti-apoptotic MCL-1 in a dose-dependent manner in Z138 cells.
YX0798 also dose-dependently suppressed phosphorylation of CDK9 substrate RNA Pol II at Ser2, but not Ser5.
YX0798 effectively inhibits the growth of patient MCL cells in cell culture and patient-derived model, triggers cell cycle arrest at G0/G1 phase.
YX0798 not only depletes the expression of oncogenic c-MYC and pro-survival MCL-1 but also drives transcriptomic reprogramming towards cell cycle dysregulation and ROS production.