Trilaciclib (hydrochloride)

Trilaciclib is an inhibitor of cyclin-dependent kinase 4 (Cdk4)/cyclin D1 and Cdk6/cyclin D3 (IC₅₀s = 1 and 4 nM, respectively).¹ It is selective for Cdk4/cyclin D1 and Cdk6/cyclin D3 over Cdk2/cyclin A, Cdk2/cyclin E, Cdk5/p25, Cdk5/p35, Cdk7/cyclin H/Mat1, and Cdk9/cyclin T (IC₅₀s = 1,290, 2,510, 1,710, 1,240, 4,640, and 50 nM, respectively). It halts the cell cycle at the G₁ phase in Cdk4/6-dependent Hs68 cells (EC₅₀ = 30 nM) but not Cdk4/6-independent A2058 cells. Trilaciclib (10-1,000 nM) prevents DNA damage and apoptosis induced by the DNA enzyme topoisomerase I inhibitor camptothecin (Item No. 11694) in Hs68 cells used as a model of Cdk4/6-dependent hematopoietic stem and progenitor cells (HSPCs). It induces reversible cell cycle arrest of HSPCs in mice when administered at doses of 50, 100, or 150 mg/kg and prevents apoptosis of bone marrow cells induced by etoposide (Item No. 12092) in mice at 100 mg/kg. Trilaciclib (150 mg/kg) also prevents myelosuppression induced by 5-fluorouracil (5-FU; Item No. 14416) in mice. Formulations containing trilaciclib have been used in the treatment of late-stage small cell lung cancer to decrease the incidence of chemotherapy-induced myelosuppression.

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1. Bisi, J.E., Sorrentino, J.A., Roberts, P.J., et al. Preclinical characterization of G1T28: A novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol. Cancer Ther. 15(5), 783-793 (2016).