Preclinical characterization of a CDK4/6/ARK5 inhibitor: on 12330

As research advances towards more specific CDK inhibitors, the need for additional targets along with CDK4/6 is immense to maximize the drug activity and provide complete remission from the disease. ON 123300 a CDK4/6/ARK5 inhibitor, has shown a promising potential in reducing the tumor burden in various cell lines (Perumal, 2016) (Athuluri-Divakar, 2016). The G1 restriction point is critical in the regulation of cell cycle which is controlled by the Rb pathway (CDK4/6-cyclin D1- Rb- p16/ink4a) and ON 123300 acts through the inhibition of phosphorylation of Rb protein. For further development and better pharmacological elucidation, a series of in vitro and in vivo studies were performed to characterize the physicochemical, pharmacokinetic and toxicity aspects of the drug. The physicochemical evaluation including pH solubility profile determination and intrinsic dissolution have provided very important information regarding the behavior of ON 123300 in physiological fluids and along the gastrointestinal tract. The pharmacokinetics of ON 123300 was studied in rats and mice which have shown good systemic exposure but with a low bioavailability of ~10% with aqueous solution of drug tested at different doses. Initial formulation development efforts have shown to increase the bioavailability of ON 123300 by 2-3-fold which strengthened the possibility of oral administration via formulation development. Further investigation of the low bioavailability along with support from the prior in vitro data confirmed the significant first pass effect and role of Cytochrome P450 enzymes, also shedding light on gender based differences in the metabolism of ON 123300. It was very well tolerated in the preclinical species up to a high dose of 400 mg/Kg upon oral administration. The preclinical absorption, distribution, metabolism & elimination data are expected to succor the future clinical investigations of ON 123300 as a promising anticancer agent.