Abstract 941: G1T28-1, a novel CDK4/6 inhibitor, protects murine hematopoietic stem and progenitor cells from cytotoxic chemotherapy

Abstract

Abstract G1T28-1 is a clinical stage, small molecule inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). Hematopoietic stem and progenitor cells (HSPC) require CDK4/6 for proliferation, allowing the transient arrest of HSPC in the G1 phase of the cell cycle by CDK4/6 inhibition. The CDK4/6 transient arrest may reduce the sensitivity of HSPC to DNA damaging chemotherapies by limiting G1 to S-phase progression in the setting of unrepaired DNA damage. A reduction in chemotherapy-induced HSPC death would in turn reduce chemotherapy-induced myelosuppression (CIM), the major dose-limiting toxicity of most cytotoxic anti-cancer agents. G1T28-1 is highly potent, exhibits exquisite selectivity, and has favorable pharmacology allowing the induction of a predictable and well-defined transient arrest of HSPC with greater uniformity and distinct profile from the arrest induced by less potent and selective CDK4/6 inhibitors. To characterize HSPC inhibition induced by G1T28-1 treatment, we studied the compound's pharmacodynamic properties in mice. Murine HSPC proliferation was measured in vivo using EdU incorporation. This work showed that G1T28-1 induces a significant, rapid and reversible G1 arrest in all early hematopoietic lineages in a dose-dependent manner. Above a determined threshold dose, higher doses do not augment the percentage of specific HSPC fractions in G1, but instead extend the duration of the block of G1 to S-phase traversal of these populations. The degree of G1 arrest differed for specific HSPC fractions, multipotent progenitors, and early lymphoid progenitors being more sensitive than populations of early myeloid and erythroid progenitors. To determine the ability of G1T28-1 to ameliorate CIM, we assessed the effect of concomitant G1T28-1 administration in a well-characterized murine model of 5FU-induced myelosuppression. A single dose of G1T28-1 given 30-minutes prior to 5FU provided multilineage protection resulting in a more rapid recovery of complete blood counts (CBCs) compared to animals who received 5FU + vehicle. This effect persisted through multiple cycles of 5FU. After four cycles of 5FU, even at count recovery, the CBC's in animals treated with vehicle + 5FU were significantly worse compared to cycle one, whereas this chronic myelosuppressive effect was completely ameliorated in animals that received G1T28-1 prior to each 5FU dose. In conclusion, we have demonstrated that G1T 28-1 is a highly potent CDK4/6 inhibitor that causes robust and transient inhibition in a broad range of HSPC. Arrest at the time of 5FU administration significantly lessens CIM; benefitting all hematopoietic lineages and attenuating the acute myelosuppression of each cycle of chemotherapy as well as reducing a chronic reduction in peripheral blood counts caused by repeated, serial chemotherapy dosing. Citation Format: Jessica A. Sorrentino, Shenghui He, John E. Bisi, Patrick J. Roberts, Jay C. Strum, Norman E. Sharpless. G1T28-1, a novel CDK4/6 inhibitor, protects murine hematopoietic stem and progenitor cells from cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 941. doi:10.1158/1538-7445.AM2015-941