A novel investigation of the cyclin A/B inhibitor ZMS-7506 demonstrates robust anti-tumor efficacy both in vitro and in vivo

Cyclins A and B are critical regulators of the transition from the S phase to the G2/M phase of the cell cycle. Abnormal expression and activity of these cyclins are hallmarks of cancer. Disruption of the interaction between E2F and the cyclin A2-CDK2 complex results in hyperactivation of E2F, leading to apoptosis and synthetic lethality in E2F-driven tumors. Small cell lung cancer (SCLC) cell lines commonly exhibit dysregulated E2F activity due to near-universal loss-of-function mutations in RB1 and TP53. We have developed ZMS-7506, a potent oral Cyclin A/B inhibitor, which demonstrated a median IC 50 of approximately 40 nM in anti-proliferation assays using a panel of SCLC cell lines. Moreover, ZMS-7506 selectively inhibited the proliferation of ovarian cancer OVCAR3 cells, with a GI 50 value below 20 nM. In the meanwhile, ZMS-7506 exhibited a GI 50 greater than 10 μM in normal human embryonic lung fibroblasts (WI38), indicating a favorable therapeutic window. Mechanistically, ZMS-7506 induced G2/M cell cycle arrest and upregulated markers associated with apoptosis and mitotic arrest, including p-KNL1, p-HH3, p-PARP, and p-gamma-H2AX. These findings suggest that ZMS-7506 activates the spindle assembly checkpoint (SAC), thereby inducing mitotic arrest and apoptosis. ZMS-7506 also exhibited moderate oral bioavailability in pre-clinical species such as dogs, which supported the oral administration in human. Moreover, ZMS-7506 exhibited robust antitumor efficacy as a monotherapy in the SCLC NCI-H69 xenograft mouse model. In summary, ZMS-7506 is a highly selective oral Cyclin A/B inhibitor with promising therapeutic potential as a monotherapy for cancers characterized by elevated E2F activity.