Lerociclib dihydrochloride (G1T38 dihydrochloride) is a potent and selective CDK4/CDK6 inhibitor, with IC50 values of 2 nM for CDK6/CyclinD3 and 1 nM for CDK4/CyclinD1.

CDK1-CyclinB1:, CDK2-CyclinE:3.6 μM, CDK4-CyclinD1:1 nM, CDK2-CyclinA:1.5 μM, CDK5-p25:1.2 μM, CDK5-p35:832 nM, CDK6-CyclinD3:2 nM, CDK9-CyclinT:28 nM

Lerociclib robustly induces sustained G1 arrest in CDK4/6 dependent cells with an EC50 of ~20 nM. A dose-dependent increase in G1 phase is observed when CDK4/6 dependent WM2664 cells are treated with G1T38 for 24 hours, maintaining this arrest up to 300 nM. WM2664 cells exhibit complete inhibition of RB phosphorylation at 30-1000 nM of Lerociclib for 24 hours compared to vehicle controls. G1T38 reduces RB phosphorylation within 1 hour post-treatment, reaching near-complete inhibition by 16 hours. G1T38 robustly inhibits proliferation in various tumor cell lines, including breast, melanoma, leukemia, and lymphoma, with EC50s as low as 23 nM. Within the CDK family, Lerociclib is least selective against CDK9/cyclin T, showing ~30-fold selectivity 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 Lerociclib 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.