| Danusertib is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases with IC50 of 13, 79, and 61 nM for Aurora A, B, and C, respectively. Danusertib exhibits potent inhibitory activity against Bcr-Abl with an IC50 of 25 nM. In HeLa cells, danusertib (0.1-10 μM) inhibits the activity on Aurora A autophosphorylation (Thr288) and Aurora B-mediated phosphorylation on histone H3 (Ser10) in a dose-dependent manner. In PC-12 cells (a nerve growth factor (NGF)-responsive cell line established from a rat pheochromocytoma), danusertib (0.6-10 μM) inhibits Trk-A phosphorylation. In several tumor cell lines covering different histotypes, including colon, breast, prostate, lung, and ovary, the GI50 values of danusertib are in the range of 28 nM (A2780) up to 300 nM (U2OS). In HCT-116 cells, treatment with danusertib (0.5 and 1 μM) increases p53 and p21 expressions in protein levels.[1] In a panel of human and murine leukemic and nonleukemic cell lines, danusertib strongly inhibits proliferation with IC50 values ranging from 50 nM to 3.06 μM. Danusertib (0.2, 0.8 and 3.2 μM) induces antiproliferative effects in BaF3-p210 cells, including imatinib-resistant M351T, E255K, and T315I mutant in a dose-dependent manner. When combination danusertib and imatinib, AED50 values for BaF3-p210, BaF3-M351T, BaF3-E255K and BaF3-T315I cells are 0.4, 0.56, 0.89 and 0.9 μM, respectively. In vivo, danusertib (15 mg/kg) significantly inhibits proliferation of K562 cells and virtually suppresses tumor growth during the 10-day treatment period. However, when the application of the danusertib is terminated, leukemic cells start to proliferate again in danusertib treatment group. But, tumor growth is less pronounced in danusertib treatment group compared with the control animals.[2] In A2780 human ovarian carcinoma xenograft in nude mice, danusertib (30 mg/kg) has a tumor growth inhibition (TGI) of 80% with maximal weight loss of 18%. In HCT-116 human colon carcinoma xenograft in nude mice, danusertib (30 mg/kg) has a tumor growth inhibition (TGI) of 66% with maximal weight loss of 22%. In HL-60 human acute myelogenous leukemia xenograft in SCID mice, danusertib (30 mg/kg) has a tumor growth inhibition (TGI) of 98% with maximal weight loss of 16%. In DMBA-induced mammary carcinoma in rat, danusertib (25 mg/kg) results in 75% inhibition of tumor growth with complete regression in one animal.[1] |
