BAY-1895344

BAY-1895344 is a potent, selective, orally active ATR inhibitor with low-nanomolar potency; potently inhibits the proliferation of a broad spectrum of human tumor cell lines with mean IC50 of 78 nM; inhibits hydroxyurea-induced H2AX phosphorylation, exhibits strong in vivo anti-tumor efficacy in monotherapy in a variety of xenograft models.Blood Cancer, Phase 1 Clinical (In Vitro) :Elimusertib potently inhibits the proliferation of a broad spectrum of human tumor cell lines with a median IC50 of 78 nM.Elimusertib potently suppresses hydroxyurea-induced H2AX phosphorylation (IC50: 36 nM) .Elimusertib shows good selectivity against mTOR (ratio of IC50 values: mTOR/ATR 61) .Elimusertib reveals high selectivity against other related kinases, such as DNA-PK (IC50: 332 nM), ATM (IC50: 1420 nM), and PI3K (IC50: 3270 nM) .Elimusertib has potent antiproliferative activity against various cancer cell lines in vitro, 25 for example in the CRC cell lines HT-29 (IC50: 160 nM) and LoVo (IC50: 71 nM), and in the B-cell lymphoma cell line SU-DHL-8 (IC50: 9 nM) . (In Vivo) :Elimusertib shows potent anti-tumor efficacy in monotherapy in a variety of xenograft models of ovarian and colorectal cancer, and causes complete tumor remission in mantle cell lymphoma models.Elimusertib (50 mg/kg; p.o.; b.i.d.; 3 days on/4 days off; for 11 days) exhibits strong antitumor efficacy in the ATM-mutated SU-DHL-8 (ATM K1964E) human GCB-DLBCL cell line derived xenograft model in mice.Elimusertib (20 mg/kg, and 10 mg/kg from day 14; p.o.; daily; 2 days on/5 days off; for 42 days) in combination with Carboplatin (40 mg/kg; i.p.; daily; 1 day on/6 days off) results in synergistic antitumor activity in the platinum-resistant ATM protein low expressing CR5038 human CRC PDX model in NOD/SCID mice.Elimusertib exhibits moderate oral bioavailability (rat 87%, dog 51%) following oral administration (rat and dog 0.6-1 mg/kg) .Elimusertib exhibits terminal elimination half-lives (mouse 0.17 h, rat 1.3 and, dog 1.0 h) due to plasma clearance (3.5, 1.2, and 0.79 L/h/kg respectively) following intravenous administration (mouse, rat and dog 0.3-0.5 mg/kg) .