Miransertib hydrochloride (ARQ-092 hydrochloride) is a powerful, orally bioavailable, selective, and allosteric inhibitor of Akt. It exhibits an inhibitory concentration (IC50) of 2.7 nM, 14 nM, and 8.1 nM against Akt1, Akt2, and Akt3, respectively. In addition to its Akt inhibitory activity, Miransertib hydrochloride also demonstrates significant potency as an inhibitor of the AKT1-E17K mutant protein. This compound shows promise in research related to PI3K/AKT-driven tumors and Proteus syndrome. Furthermore, Miransertib hydrochloride displays efficacy against Leishmania [1, 2].

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 (5 mg/kg) and monkeys (10 mg/kg), achieving absorption rates of 62% and 49%, respectively. In rats, it exhibits a half-life of 17 hours, longer than the 7 hours observed in monkeys. Concentration peaks reach 198 ng/mL in rats and 258 ng/mL in monkeys, with area under the curve (AUC) values recorded at 5496 h ng/mL and 2960 h ng/mL for each species. Additionally, Miransertib has been shown to effectively inhibit tumor growth in a human xenograft mouse model of endometrial adenocarcinoma [1].