Description
BAY 1000394 is an orally bioavailable pan-CDK inhibitor for CDK1/2/3/4/7/9 with IC50 of 5-25 nM. It also potently inhibits Aurora A, Clk2, ARK5, FGFR1, Flt3, and JAK2/3. Phase 1/2.
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Targets
CDK1, CDK2, CDK4, CDK9, CDK7
IC50
7 nM; 9 nM; 11 nM; 5 nM; 25 nM
Molecular Formula
C18H21F3N4O3S
Chemical Name
2-Butanol, 3-[[2-[[4-[[S(R)]-S-cyclopropylsulfonimidoyl]phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-, (2R,3R)-
Solubility
DMSO mg/mL; Water mg/mL; Ethanol mg/mL
In vitro
BAY 1000394 inhibits the kinase activity of the cell-cycle CDKs CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D with IC50 values of 7, 9, and 11 nM, respectively. The transcriptional CDKs CDK9/cyclin T1 and CDK7/cyclin H/MAT1 are also inhibited by BAY 1000394 in a similar range (5 and 25 nM), as well as the other CDK family members, classifying BAY 1000394 as a pan-CDK inhibitor. BAY 1000394 simultaneously inhibits cell-cycle progression and of RNA polymerase II-mediated gene transcription. On a panel of 214 non-CDK Ser/Thr and Tyr kinases, 16 additional kinases are found to be inhibited by BAY 1000394 with IC50 values below 100 nM. BAY 1000394 displays broad and uniform inhibitory activity on cancer cell proliferation with IC50s values between 9 and 79 nM (mean 39 nM) for a panel of 40 human lung tumor cell lines, and IC50s between 6 an d 84 nM (mean 37 nM) for a panel of 24 human breast tumor and immortalized cell lines. Within these panels, which represent a broad range of genetic backgrounds (p53, pRB, K-Ras, PGP, etc.), no cell line could be identified that is poorly sensitive towards treatment with BAY 1000394. Antiproliferative activity of BAY 1000394 is associated with the induction of apoptotic cell death. Exposure of asynchronously growing HeLa cells to BAY 1000394 for 24 hours reduces the fraction of cells with 2N content, from 69% to 52% compared with vehicle treated cells and strongly increases the fraction of cells with less than 2N DNA content from 1% to 16%. Only minor shifts are observed for cells in S, G2, or M phase.
In vivo
BAY 1000394 shows potent tumor growth inhibition in monotreatment upon oral application in various dosing schedules in a dose-dependent manner, activity in models of treatment-refractory tumors, and efficacy in cell-line–derived as well as in patient tumor–derived models. BAY 1000394 (2 mg/kg) suppresses growth of HeLa-MaTu xenografts tumor with T/C values of 0.03 and signs of tumor regression. BAY 1000394 shows additive efficacy in combination with cisplatin. Addition of BAY 1000394 to cisplatin results in a strong tumor growth inhibition of NCI-H82 SCLC xenograft tumors with T/C values of 0.01 (1.0 mg/kg BAY 1000394) and -0.02 (1.5 mg/kg BAY 1000394).
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