生物活性

• 描述The AGC kinases AKT1, AKT2, and AKT3 are key mediators of the PI3K/AKT/mTOR signaling pathway, which promotes diverse physiological processes such as proliferation, migration, antiapoptotic survival, and protein synthesis. Allosteric inhibitors offer a unique advantage over ATP-competitive inhibitors in that very high kinase selectivity can be achieved by targeting a distinct allosteric pocket in AKT formed by the pleckstrin homology (PH) and kinase domains. Miransertib (ARQ 092) is an investigational orally available potent and selective allosteric pan‐AKT inhibitor that inhibits both the active and inactive forms of AKT1, AKT2, and AKT3 with biochemical IC50 values of 5.0, 4.5, and 16 nM, respectively^[5]. Miransertib reduced phosphorylation of AKT and downstream targets of AKT in a concentration‐dependent manner. It showed strong affinity for unphosphorylated full-length AKT1 and potently inhibited the phosphorylated form of full-length AKT isoforms. Miransertib demonstrated high enzymatic potency against AKT1, AKT2, and AKT3, as well as potent cellular inhibition of AKT activation and the phosphorylation of the downstream target PRAS40, and also served as a potent inhibitor of the AKT1-E17K mutant protein inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma^[6]. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50 – 500 nM Miransertib significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets^[7]. Treatment with Miransertib at a dose of 15 mg/kg/day for 7 days every other week can significantly inhibit the tumor growth of HCC^[8].
• 作用机制Miransertib binds to the allosteric pocket formed by the kinase and PH domains. The aminopyrimidine group of the core moiety forms a bidentate hydrogen bonding interaction with the main chain atoms of loop of β4-strand and αC-helix. The phenylcyclobutylamine side chain associates with the conserved YRD motif of kinase domain by polar and nonpolar interactions^[5].

• 动物研究
  剂量	Mice: 50 mg/kg - 100 mg/kg[3] (p.o.); 5 mg/kg[4] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Rats[4] Monkeys[4] Dose 5 mg/kg 10 mg/kg Administration p.o. p.o. F 0.62 0.49 AUCinf 5496 h·ng/ml 2960 h·ng/ml T1/2 17 h 7 h Tmax 8.0 h 4.3 h Cmax 198 ng/ml 258 ng/ml