tcsc0152 Danusertib

Danusertib is a pyrrolo-pyrazole and aurora kinase inhibitor with IC₅₀ of 13, 79, and 61 nM for Aurora A, B, and C, respectively.

IC50 & Target: IC50: 13 nM (Aurora A), 79 nM (Aurora B), 61 nM (Aurora C)^[1]

In Vitro: Danusertib (0.01 to 50 μM) significantly decreases viability of C13 and A2780cp cells. The IC₅₀s are 10.40 and 1.83 μM for C13 cells, and 19.89 and 3.88 μM for A2780cp cells after 24- and 48-h treatment. Danusertib induces cell cycle arrest in G2/M phase in C13 and A2780cp cells. Danusertib treatment results in a marked increase in the percentage of cells arrested in G2/M phase and an accumulation of polyploidy in C13 and A2780cp cells. Danusertib demotes the expression of CDK1/CDC2 and cyclin B1 but promotes the expression of p21 Waf1/Cip1, p27 Kip1, and p53. Danusertib induces autophagy in C13 and A2780cp cells with the involvement of PI3K/Akt/mTOR signaling pathway^[1]. PHA-739358 strongly inhibits proliferation of all leukemic cell lines tested, with IC₅₀ values ranging from 0.05 μM to 3.06 μM. PHA-739358 induces antiproliferative effects in BaF3-p210 cells, including IM-resistant M351T, E255K, and T315I mutants. PHA-739358 (5 μM) reduces phosphorylation of CrkL in BaF3-p210 wt cells and IM-resistant mutants^[2]. Danusertibsertib leads to cell-cycle arrest and completely inhibits cell proliferation of the GEP-NET cells in vitro^[3].

In Vivo: PHA-739358 (15 mg/kg twice a day, i.p.) and IM are well tolerated, and significantly inhibit proliferation of K562 cells andvirtually suppressed tumor growth during the 10-day treatment period^[2]. In a subcutaneous murine xenograft model, danusertibsertib (2×15 mg/kg/d, i.p.) significantly reduces tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil^[3].