Miransertib

Miransertib (ARQ-092) is a potent, selective and allosteric inhibitor of Akt1/2/3 with IC50 of 5/4.5/16 nM respectively; inhibits cellular AKT activation and the phosphorylation of the downstream target PRAS40; inhibits tumor growth in a human xenograft mouse model of endometrial adenocarcinoma; orally bioavailable.Blood Cancer Phase 1 Clinical (In Vitro) :In a large panel of cell lines derived from various tumor types, Miransertib (ARQ-092; Compound 21a) shows potent anti-proliferative activity in cell lines containing PIK3CA/PIK3R1 mutations compared to those with wild-type (wt) PIK3CA/PIK3R1 or PTEN loss. Miransertib shows excellent inhibition of p-Akt (S473) and p-Akt (T308) in both AN3CA and A2780 cells. The inhibition of the downstream protein p-PRAS40 (T246) is observed with Miransertib (IC50=0.31 μM) .Miransertib is markedly effective against intracellular amastigotes of L. donovani or L. amazonensis-infected macrophages. Miransertib also enhances mTOR dependent autophagy in Leishmania-infected macrophages (In Vivo) :Miransertib (ARQ-092; Compound 21a) shows good absolute oral bioavailability in rats (5 mg/kg) and monkeys (10 mg/kg) with F values of 62% and 49%, respectively. The half-life is longer in rats compared to monkeys with t1/2 values of 17 h in rats versus 7 h in monkeys. The Cmax is 198 ng/mL and 258 ng/mL and the AUCinf was 5496 h ng/mL and 2960 h ng/mL in rats and monkeys, respectively.Miransertib (ARQ-092; Compound 21a) inhibits tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.