Abstract 1524: A first-in-class CDK4 inhibitor shows excellent in vitro and in vivo efficacy against ovarian cancer

Abstract

Abstract Ovarian cancer is one of the most common malignancies, accounting for more deaths than any other cancer of the female reproductive system. Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various cancers. Over-expression of CDK4/6 &/or cyclin D1 is commonly observed in ovarian cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian cancer whose tumor demonstrated Rb-positive & a low expression of p16INK4a have the worst clinical outcome, but these patients are likely to gain benefit from CDK4/6 inhibition. Here, we describe the preclinical development of 2-94; a potent, highly selective and orally bioavailable CDK4 inhibitor for the treatment of ovarian cancer. Specifically, 2-94 exhibits high selectivity for CDK4/D1 (Ki = 2 nM) over CDK6/D3 (Ki = 279 nM). Consistent with a CDK4-targeted mechanism, 2-94 potently inhibited proliferation of Rb proficient ovarian cancer cells. It induced G1 cell cycle arrest by reducing Rb phosphorylation at S780, S795 and S807/11 residues in a dose dependent manner. Apoptosis was induced with evident increase of caspase 3/7 activity and reduction of Bcl-2 protein levels in A2780 cells. In addition, 2-94 has shown synergistic activity with mTOR, MEK, PI3K and PARP inhibitors. In contrast, no apparent cell cycle effect, senescence or apoptosis was observed in human bone marrow mononuclear (hBMNCs) cells by 2-94 treatment unlike palbociclib and ribociclib which increased the G1 population of hBMNCs, suggesting the low toxicity of 2-94 compared to clinical compounds. Consistent with its favourable pharmacokinetic properties and high oral bioavailability, 2-94 delayed tumor growth and significantly increased the survival of A2780 tumor bearing nude mice by oral administration. 2-94 was more efficacious when compared to palbociclib, resulting in a T/C = 22% for 2-94 vs T/C = 31% for palbociclib. Moreover, 2-94 showed little or no effect on lymphocyte and neutrophil counts whilst palbociclib caused their reduction. This lower effect of 2-94 on the neutrophils and lymphocytes might be due to its lesser effect on CDK6-cyclin D3 compared to palbociclib. Both 2-94 and palbociclib didn't cause histopathological changes in the bone marrow, intestine, liver, heart and kidney of the mice. Pharmacodynamical studies confirmed that 2-94 reduced the Rb phosphorylation at S780, S795 and S807/811 in the tumour models. In conclusion, 2-94 is a first-in-class CDK4 inhibitor with high selectivity against a panel of 360 human kinases. This selectivity can be taken as a reason for the observed better safety of 2-94 compared to palbociclib. The favourable oral pharmacokinetics, robust antitumor efficacy and excellent safety profiles make 2-94 a highly attractive candidate for development towards the clinic. Citation Format: Laychiluh B. Mekonnen, Solomon Zeleke, Jimma Lenjisa, Mingfeng Yu, Benjamin Noll, Gary Heinemann, Robert Milne, Hugo Albrecht, Martin K. Oehler, Shudong Wang. A first-in-class CDK4 inhibitor shows excellent in vitro and in vivo efficacy against ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1524.