Advancements in Targeted Cancer Therapy: The Emergence of G1T38 as an Effective CDK4/6 Inhibitor for Rb Competent Tumors

The discovery of effective cyclin-dependent kinase (CDK) inhibitors has been impeded by challenges in target and structural biology, often resulting in drugs with limited efficacy and high toxicity. A first-generation CDK4/6 inhibitor, palbociclib, has shown high efficacy in treating ER+/HER2- metastatic breast cancer but causes severe myelosuppression, necessitating treatment breaks and risking tumor growth and drug resistance.

To address these issues, a new compound, G1T38, has been developed. G1T38 is an orally administered, potent, and selective CDK4/6 inhibitor with unique properties that maintain antitumor efficacy while minimizing effects on bone marrow proliferation. It is a competitive, nanomolar inhibitor of CDK4/6 with high selectivity for CDK4-cyclin D1 and CDK6-cyclin D3 complexes and demonstrates on-target selectivity across a kinome panel.

G1T38 induces a precise G1 cell cycle arrest and loss of Rb phosphorylation in Rb competent cells without affecting Rb deficient cells. It shows low EC50 values in Rb competent cell lines and significant, durable growth inhibition of tumors in preclinical models, including a HER2/neu genetically engineered mouse model (GEMM) and MCF7 xenograft breast cancer models. The compound is cleared from plasma but accumulates in tumors, correlating with reduced Rb phosphorylation and tumor cell proliferation.

Moreover, G1T38 has shown a dose-dependent decrease in neutrophils without causing severe neutropenia in daily oral dosing studies in mice, rats, and dogs over 28 days.

The unique pharmacokinetic and pharmacodynamic profile of G1T38 allows for high antitumor efficacy with mild effects on bone marrow, making it a promising candidate for a daily oral antineoplastic agent for the treatment of Rb competent tumors.