Miransertib hydrochloride (ARQ-092 hydrochloride) is a potent, orally bioavailable, selective, and allosteric inhibitor of Akt with an IC50 of 2.7 nM, 14 nM, and 8.1 nM against Akt1, Akt2, and Akt3, respectively. It also shows significant potency against the AKT1-E17K mutant protein and holds promise for research on PI3K/AKT-driven tumors and Proteus syndrome. Additionally, Miransertib hydrochloride exhibits efficacy against Leishmania [1, 2].

Akt1:2.7 nM, Akt3:8.1 nM, Akt2:174 nM

In a comprehensive study involving various tumor-derived cell lines, Miransertib (ARQ-092; Compound 21a) demonstrated significant anti-proliferative effects in cell lines harboring mutations in PIK3CA/PIK3R1 compared to those with the wild-type (wt) PIK3CA/PIK3R1 or PTEN deficiency. Additionally, Miransertib effectively inhibited p-Akt (S473) and p-Akt (T308) in AN3CA and A2780 cells and suppressed p-PRAS40 (T246) with an IC 50 of 0.31 μM. Notably, Miransertib was highly effective against intracellular amastigotes of L. donovani or L. amazonensis in infected macrophages and promoted mTOR-dependent autophagy in Leishmania-infected macrophages, highlighting its diverse therapeutic potential.

Miransertib (ARQ-092; Compound 21a) demonstrates effective oral bioavailability in rats (62%, 5 mg/kg) and monkeys (49%, 10 mg/kg), with half-lives of 17 hours and 7 hours, respectively. Peak plasma concentrations are 198 ng/mL in rats and 258 ng/mL in monkeys, with AUC values of 5496 h·ng/mL and 2960 h·ng/mL, respectively. Additionally, Miransertib effectively inhibits tumor growth in a human xenograft mouse model of endometrial adenocarcinoma [1].