Abstract LB-A21: Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300

Abstract

Abstract Introduction: Recent proof-of-concept for targeting cyclin dependent kinases 4 and 6 (CDK4/6) culminated in the approval for breast cancer of the first-in-class CDK4/6 inhibitor, palbociclib (Ibrance®). Palbociclib and other potent but narrowly targeted CDK4/6 inhibitors are cytostatic rather than cytotoxic (Leonard et al, 2012), and require combination therapy for optimal activity. ON 123300 is a next-generation CDK4/6 inhibitor with improved single-agent cytotoxicity. This novel compound is a potent CDK4 and CDK6 inhibitor (IC50 = 3.9 nM and 9.8 nM, respectively) that is cytotoxic against breast and other cancer cell lines (Reddy et al, 2014). We present pre-IND profiling pharmacology, physicochemical and ADME studies to support ON 123300 as a clinical candidate and next-generation CDK4/6 inhibitor. Methods and Results: Non-clinical studies were conducted in order to assess the drug-like properties of ON 123300 and its pharmaceutical salts. Physicochemical parameters were determined for the compound. ON 123300 was highly soluble below pH 4.0, with reduced solubility in more basic conditions. Predicted intestinal absorption, as measured by Caco-2 permeability, was 1.95×10-5 cm/s with a low efflux ratio. Based on these characteristics, the compound was advanced to lead profiling against 68 primary molecular targets. Radioligand binding studies revealed limited receptor inhibition (11/68 targets) with 10 μM of ON 123300. Human Ether-a-go-go (hERG) inhibition testing revealed no significant effect (IC50 > 25 μM). In vitro metabolism studies indicated metabolism through CYP3A4 and CYP2C8. Finally, in silico based modeling (Cloe® PK) integrating all key non-clinical parameters was carried out in order to estimate the potential for oral absorption in humans. Preliminary analysis suggests good oral bioavailability and the potential to establish an acceptable therapeutic window. Conclusions: The well differentiated biochemical, anticancer and pharmaceutical properties of ON 123300 provide the basis for pre-clinical toxicology testing, leading to an investigational new drug (IND) filing and clinical exploration of this compound across tumor types that share targets accessed by this next-generation CDK inhibitor. Citation Format: Benjamin Hoffman, Ramana Reddy, Muralidhar Mallireddigari, Daniel Fox, Chen Ren, Manoj Maniar. Single-agent activity and favorable pharmaceutical properties of orally bioavailable next-generation CDK4/6 inhibitor, ON 123300. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A21.