Simurosertib (TAK-931)

Simurosertib is an inhibitor of cell division cycle 7 (Cdc7) kinase (IC₅₀ = 0.26 nM).¹ It is selective for Cdc7 over cyclin-dependent kinase 2 (Cdk2) and Rho-associated kinase 1 (ROCK1; IC₅₀s = 6,300 and 430 nM, respectively). It inhibits phosphorylation of DNA replication licensing factor MCM2 in HeLa cells (IC50 = 17 nM) and reduces proliferation of COLO 205 cells (EC₅₀ = 81 nM). Simurosertib induces replication stress, halts the cell cycle at the G₂/S phase, and inhibits the growth of a wide variety of cancer cells (GI₅₀s = 30.2->10,000 nM).² It reduces intratumor levels of phosphorylated MCM2 in COLO 205 and SW948 mouse xenograft models when administered at a dose of 80 mg/kg and reduces tumor growth in the same models when administered at doses of 40 or 60 mg/kg twice per day.

1.Kurasawa, O., Miyazaki, T., Homma, M., et al.Discovery of a novel, highly potent, and selective thieno[3,2- d]pyrimidinone-based cdc7 inhibitor with a quinuclidine moiety (tak-931) as an orally active investigational antitumor agentJ. Med. Chem.63(3)1084-1104(2020) 2.Iwai, K., Nambu, T., Dairiki, R., et al.Molecular mechanism and potential target indication of TAK-931, a novel CDC7-selective inhibitorSci. Adv.5(5)eaav3660(2019)