Research Project
8336811
DESCRIPTION (provided by applicant): Syndrome (ARS), including a lethal myelosuppression due to the sensitivity of proliferating hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation (IR). No effective therapy exists to mitigate the hematologic toxicities of TBI. Herein G-Zero Therapeutics seeks to further the proprietary development of small molecule inhibitors of cyclin-dependent kinase 4 (CDK4) and CDK6 which have recently been demonstrated to ameliorate ARS and rescue survival of mice after lethal-dose TBI. CDK4/6 inhibitors induce selective cellular quiescence increasing radioresistance of human cell lines in vitro and mice in vivo. Treatment of wild-type mice with CDK4/6 inhibitors induces reversible pharmacological quiescence (PQ) of early HSPCs but not most other cycling cells in the bone marrow or other tissues. Selective PQ of HSPCs decreases the hematopoietic toxicity of TBI, even when administered well after TBI. These results demonstrate an effective method to mitigate the hematopoietic toxicity of IR in mammals. In this proposal, we seek to optimize DMPK of G-Zero's CDK4/6 small molecule inhibitors to ensure sufficient pharmacokinetic (PK) properties (T1/2 >4hrs, oral bioavailability >40%, and an attainable peak serum concentration at least 10 fold higher than its in vitro IC50). Evaluation of inhibitors for acute induction of PQ (a 4-fold or greater increase in the frequency of HSPC in the G0/G1 phase of the cell cycle at 24 hours post-gavage without increased cell death) will serve as a pharmacodynamic (PD) marker for in vivo efficacy. Using compounds that pass these PK and PD screens, non-GLP rodent efficacy studies will be assessed using survival and protection of blood cell counts when administered post-IR. The successful candidate will be formulated, tested for stability and manufactured under GMP conditions. This proposal will identify a commercially valuable lead candidate to provide IND-enabling preclinical animal data in support of G- Zero's capability to provide an effective radiomitigant: a simple and non-toxic pill that will enhance survival when taken up to 24 hours after lethal doses of TBI
