Miransertib (hydrochloride)

Miransertib hydrochloride (ARQ-092 hydrochloride) is a potent, orally active, selective and allosteric Akt inhibitor with IC₅₀s of 2.7 nM, 14 nM and 8.1 nM for Akt1, Akt2, Akt3, respectively. Miransertib hydrochloride is also a potent the AKT1-E17K mutant protein inhibitor and has the potential for PI3K/AKT-driven tumors and Proteus syndrome research^[1]. Miransertib hydrochloride is effective against Leishmania^[2]. 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)^[1].
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^[2]. 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 t_1/2 values of 17 h in rats versus 7 h in monkeys. The C_max is 198 ng/mL and 258 ng/mL and the AUC_inf was 5496 h?ng/mL and 2960 h?ng/mL in rats and monkeys, respectively^[1].
Miransertib (ARQ-092; Compound 21a) inhibits tumor growth in a human xenograft mouse model of endometrial adenocarcinoma^[1].