Lerociclib (G1T38) is a potent and selective inhibitor of CDK4/6, with IC50s of 2nM, 1 nM for CDK6/CyclinD3 and CDK4/CyclinD1, respectively.

Lerociclib produces a robust and sustained G1 arrest in CDK4/6 dependent cells with an EC50 of ~20 nM.?A dose dependent increase of cells in the G1 phase of the cell cycle is observed when CDK4/6 dependent WM2664 cells are treated with Lerociclib for 24 hours.?This arrest is maintained through 300 nM, more than 300x the biochemical IC50.?WM2664 cells treated with 30-1000 nM of Lerociclib for 24 hours exhibits a complete inhibition of RB phosphorylation compared to vehicle controls.?Treatment with Lerociclib reduces RB phosphorylation within 1 hour post-treatment and generates near complete inhibition of RB phosphorylation by 16 hours post-treatment.?Lerociclib produces a robust inhibition of proliferation in a diverse array of tumor cell lines including breast, melanoma, leukemia and lymphoma with EC50 concentrations as low as 23 nM.Within the CDK family, Lerociclib is least selective against CDK9/cyclin T, ~30 fold between CDK4/cyclin D1 and CDK9/ cyclin T at the biochemical IC50.

In this HER2+ breast cancer model, Mice treated with Lerociclib elicits 8% tumor regression after 21 days of treatment while control animals have a 577% increase in tumor burden over the same treatment period.?Compared to the vehicle-treated mice, daily treatment with 100 mg/kg of Lerocyclib or palbociclib shows tumor regression within 10 days in the MCF7 xenograft model.?After 27 days of treatment, tumor growth inhibition is observed in the 10, 50, and 100 mg/kg Lerociclib cohorts (approximately 12%, 74%, and 90% inhibition, respectively).?Daily oral palbociclib treatment causes an 18%, 66%, and 87% tumor growth inhibition in the 10, 50, and 100 mg/kg dosage cohorts, respectively.