Background:

CYC065 is a second-generation, orally available ATP-competitive inhibitor of CDK2/CDK 9 kinases.

CYC065 blocks cells in the G1 phase of the cell cycle and inhibits cell growth specifically in cyclin E1 (CCNE1)-overexpressing uterine serous carcinomas (USCs). USC cell lines expressing high CCNE1 mRNA and protein levels to be significantly more sensitive to treatment with CYC065 in vitro when compared with low CCNE1-expressing cell lines (IC50: mean±s.d.=124.1±57.8 nM in CCNE1-overexpressing USC cell lines vs 415±117.5 nM in CCNE1 low expressors, respectively; P=0.0003). Importantly, low concentrations of CYC065 (i.e., 100 nM) causes an arrest in the G1 phase of the cell cycle only in the CCNE1-overexpressing USC cell lines (i.e., USC-ARK-2, USC-ARK-7) [1].

To evaluate the therapeutic potential of CYC065 as a single agent, USC-ARK-2-derived xenografts are treated daily with CYC065 (22.5 mg/kg) for a 3-week period. Tumor size and mouse weight are recorded two times a week. The daily administration of CYC065 results in a significant reduction of tumor growth compared with the vehicle-treated mice (P=0.012 starting at day 9 of the treatment). No significant weight loss is reported during the entire treatment period[1].

[1]. Cocco E, et al. Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. Br J Cancer. 2016 Jul 26;115(3):303-11.