G1T38

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

G1T38 (Lerociclib, G1T 38) 是一种新型、有效、选择性的 CDK4/6 抑制剂，对 CDK4/cyclin D1 和 CDK6/cyclin D3 的生化 IC50 分别为 1 nM 和 2 nM。

G1T38 (Lerociclib, G1T 38) is a novel, potent and selective inhibitor of CDK4/6 with biochemical IC50 of 1 nM and 2 nM for CDK4/cyclin D1 and CDK6/cyclin D3, respectively; shows weak inhibitory effect on CDK9/cyclin T (IC50=28 nM) and CDK5/p35 (IC50=832 nM), >1,000-fold selectivity over CDK1/2/7; decreases RB1 phosphorylation, causes G1 arrest, and inhibits cell proliferation in a variety of CDK4/6-dependent tumorigenic cell lines; demonstrates equivalent or improved tumor efficacy compared to palbociclib in an ER+ breast cancer xenograft model.Breast Cancer,Phase 2 Clinical

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. 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.

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. Interestingly, at 50 mg/kg, Lerociclib is significantly more efficaciou than palbociclib. Similar results are seen in the ER+ZR-75-1 breast cancer xenograft model when comparing Lerocyclib and palbociclib at the 50 mg/kg dose. Lerociclib treated mice exhibits 77% TGI with an overall 60% tumor growth delay demonstrating Lerocyclib alone is highly efficacious in this NSCLC tumor model.

Lerociclib | G1T 38

Cell Cycle/DNA Damage

CDK

CDK

Cancer

Breast Cancer

1628256-23-4

474.613

C26H34N8O

>98% (HPLC)

——

CC(C)N1CCN(CC1)C2=CN=C(C=C2)NC3=NC=C4C=C5C(=O)NCC6(N5C4=N3)CCCCC6

2'-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one

(-20℃)

With Ice Pack

≥ 2 years