Organismal Radioprotection Through Pharmacological Quiescence

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 hematologictoxicities 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 afterlethal-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 earlyHSPCs 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 gt4hrs, oral bioavailability gt40%, and an attainable peak serum concentrationat 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 serveas 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 effectiveradiomitigant: a simple and non-toxic pill that will enhance survival when taken up to 24 hours after lethal doses of TBI PUBLIC HEALTH RELEVANCE: Exposure to significant levels of total body irradiation (TBI) induces a lethal acute radiation syndrome (ARS). No effective therapy exists to mitigate the hematologic toxicities of TBI. Herein G-Zero Therapeutics seeks to further the proprietary development of drugs which have recently been demonstrated to ameliorate ARS and rescue survival after lethal-dose TBI. 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 therapeutic for hematologic radiation toxicity: a simple and non-toxic pill that will enhance survival when taken up to 24 hours after lethal dose TBI.