Abstract 2824: G1T38, a novel, oral, potent and selective CDK4/6 inhibitor for the treatment of Rb competent tumors
Authors: Sorrentino Jessica A. , Bisi John E. , Roberts Patrick J. , Strum Jay C. 
Published: July 2016

Abstract
The development of therapeutically effective inhibitors of the cyclin dependent kinase (CDK) family has been challenging due to a poor understanding of target and structural biology leading to the development of drugs that are toxic with limited efficacy. Recently, the first highly selective CDK4/6 inhibitor, palbociclib, was approved by the FDA for use in combination with letrozole as a first line treatment in patients with ER+/ HER2- metastatic breast cancer. While this first approved CDK4/6 inhibitor is highly efficacious, it causes severe myelosuppression during daily treatment resulting in at least a 7 day treatment holiday in every 28 day cycle to allow recovery of neutrophil counts. This leads to an increased risk of febrile neutropenia, potential tumor growth during the treatment holiday, and emergence of drug resistance. CDK4/6-induced myelosuppression is the result of on-target inhibition of hematopoietic stem and progenitor cell proliferation causing a narrow therapeutic window between tumor efficacy and neutropenia. Thus, a next generation CDK4/6 inhibitor will need to produce a potent, selective G1 arrest in Rb competent tumors while minimizing the effect on the bone marrow.
With a new understanding of CDK4/6 biology, we have generated compounds with unique properties that maintain tumor efficacy while minimizing inhibition of bone marrow proliferation. Here we describe G1T38, a novel, oral, potent, and selective CDK4/6 inhibitor. Biochemical profiling demonstrates G1T38 is a competitive, nanomolar inhibitor of CDK4/6 with highly selectivity for CDK4-cyclin D1 and CDK6-cyclin D3. Kinome profiling exhibits on-target selectivity across 468 independent kinases at 100 nM, with no significant activity against other cell cycle or mitotic kinases. G1T38 elicits a precise G1 arrest profile along with loss of Rb phosphorylation in Rb competent cells with no impact in Rb deficient cells up to three orders of magnitude above the biochemical IC50. In cell proliferation assays, G1T38 exhibits a low EC50 (&lt;100 nM) in Rb competent cell lines compared to &gt;3 μM in Rb null cells. In vivo, daily oral treatment with G1T38 causes significant, durable growth inhibition of tumors in a HER2/neu GEMM and in MCF7 xenograft breast cancer models. G1T38 is cleared from the plasma but significantly accumulates in tumors. The level of G1T38 in the tumor correlates with significant reductions in Rb phosphorylation and tumor cell proliferation. Additionally, daily oral dosing of G1T38 in mice, rats and dogs for up to 28 days has shown a dose dependent decrease in neutrophils without severe neutropenia.
These data demonstrate that the unique pharmacokinetic and pharmacodynamic properties of G1T38 allow it to be highly efficacious against tumors while having a mild effect on the bone marrow, thus making it optimal for use as a daily oral antineoplastic agent.
Citation Format: Jessica A. Sorrentino, John E. Bisi, Patrick J. Roberts, Jay C. Strum. G1T38, a novel, oral, potent and selective CDK4/6 inhibitor for the treatment of Rb competent tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2824.