Psychiatry

Grant Detail

This is a chronological listing of grants held by this department, with the most recent listed first. New grants appear in this list weekly and contribute related to the department's Research Profile. The source of grants for this application comes directly from your institution.

SBIR-NIAID Advanced Technology SBIR

Norman Sharpless

Exposure to significant levels of total body irradiation (TBI) induces acute radiation 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 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 literally rescue mice from otherwise lethal TBI. More specifically, 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 induced reversible pharmacological quiescence (PQ) of early HSPCs but not most other cycling cells in the bone marrow or other tissues. Selective PQ of HSPCs decreased the hematopoietic toxicity of TBI, even when the CDK4/6 inhibitor was administered 20 hours 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 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 potent increase in G0/G1 staged bone marrow derived HSPC cells as evidenced by a 4-fold or greater decrease in EdU incorporation and Ki67 expression at 24 hours post-gavage that also does not increase HSPC cell death (>2%), will serve as proof of concept. Non-GLP rodent efficacy will be assessed using survival and protection of blood cell counts. 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 therapeutic for radiation toxicity: a simple and non-toxic pill that will enhance survival when taken up to 24 hours after IR exposure.