Atuveciclib (BAY-1143572) is potent and highly selective PTEFb/CDK9 inhibitor with IC50 values of 13 nM for CDK9/CycT and the ratio of IC50 values for CDK2/CDK9 is about 100. Outside the CDK family, It inhibits GSK3 kinase with IC50 values of 45 nM and 87 nM for GSK3α and GSK3β respectively.
BAY?1143572 is a potent and highly selective CDK9 inhibitor (IC50 CDK9/CycT1: 13?nM, ratio of IC50 values CDK2/CDK9: 100). Outside the CDK family, submicromolar inhibitory activity was only recorded against GSK3 kinase (IC50 GSK3α: 45?nM, GSK3β: 87?nM). BAY?1143572 demonstrates antiproliferative activity against HeLa cells (IC50 = 920?nM) and MOLM-13 cells (IC50 = 310?nM). It also demonstrates improved Caco-2 permeability and a decreased efflux ratio (PappA→B: 35?nm/s, ER: 6) relative to lead compound BAY‐958 (PappA→B: 22?nm/s, ER: 15)[1].
In an in?vivo pharmacokinetic study in rats, BAY?1143572 showed low blood clearance (CLb 1.1?L/h/kg). The volumes of distribution (Vss) of BAY?1143572 is 1.0?L/kg. BAY?1143572 shows significantly improved oral bioavailability of 54?%. The blood/plasma ratios is about 1. It does not show significant inhibition of cytochrome P450 activity, with IC50 values >20?μM[1]. The administration of BAY 1143572 in immunocompromized NOD/Shi-scid/IL-2Rγ null (NOG) mice xenografted with patient-derived ATL cells greatly reduced the infiltration of ATL cells into organs, such as liver and bone marrow. Decreased human soluble IL2R levels in serum were also observed, which indicated a reduction of ATL tumor burden[2].
[1] Lücking U, et al. ChemMedChem. 2017, 12(21):1776-1793. [2] Wong RWJ, et al. Molecules. 2018, 23(5). pii: E1057.