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

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02594215	Proteus Syndrome	Phase 1	Active, not recruiting	December 1, 2025	United States, Maryland ... more >> National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland, United States, 20892 Collapse <<
  NCT03317366	-	-	-	-	-
  NCT03094832	Proteus Syndrome ... more >> PIK3CA-Related Overgrowth Spectrum (PROS) Collapse <<	Phase 1 Phase 2	Recruiting	June 2020	United States, Massachusetts ... more >> Boston Children's Hospital Recruiting Boston, Massachusetts, United States, 02115 Contact: ArQule    781-994-0300    ClinicalTrials@arqule.com    Italy Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele" Withdrawn Catania, Italy Fondazione Policlinico Universitario Agostino Gemelli Recruiting Roma, Italy, 00168 Contact: ArQule    781-994-0300    ClinicalTrials@arqule.com    Ospedale Bambino Gesu Recruiting Rome, Italy Contact: ArQule    781-994-0300    ClinicalTrials@arqule.com Collapse <<

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• 参考文献

• [1] Kim K, Li J, et al. ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease. Haematologica. 2017 Feb;102(2):246-259.

  [2] Yu Y, Savage RE, et al. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092. PLoS One. 2015 Oct 15;10(10):e0140479.

  [3] Yu Y, Hall T, et al. In-vitro and in-vivo combined effect of ARQ 092, an AKT inhibitor, with ARQ 087, a FGFR inhibitor. Anticancer Drugs. 2017 Jun;28(5):503-513.

  [4] Lapierre JM, Eathiraj S, et al. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. J Med Chem. 2016 Jul 14;59(13):6455-69.

  [5] Leoni C, Gullo G, Resta N, Fagotti A, Onesimo R, Schwartz B, Kazakin J, Abbadessa G, Crown J, Collins CD, Ranieri C, Scambia G, Zampino G. First evidence of a therapeutic effect of miransertib in a teenager with Proteus syndrome and ovarian carcinoma. Am J Med Genet A. 2019 Jul;179(7):1319-1324.

  [6] Lapierre JM, Eathiraj S, Vensel D, Liu Y, Bull CO, Cornell-Kennon S, Iimura S, Kelleher EW, Kizer DE, Koerner S, Makhija S, Matsuda A, Moussa M, Namdev N, Savage RE, Szwaya J, Volckova E, Westlund N, Wu H, Schwartz B. Discovery of 3-(3-(4-(1-Aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT Inhibitor. J Med Chem. 2016 Jul 14;59(13):6455-69.

  [7] Kim K, Li J, Barazia A, Tseng A, Youn SW, Abbadessa G, Yu Y, Schwartz B, Andrews RK, Gordeuk VR, Cho J. ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease. Haematologica. 2017 Feb;102(2):246-259.

  [8] Roth GS, Macek Jilkova Z, Zeybek Kuyucu A, Kurma K, Ahmad Pour ST, Abbadessa G, Yu Y, Busser B, Marche PN, Leroy V, Decaens T. Efficacy of AKT Inhibitor ARQ 092 Compared with Sorafenib in a Cirrhotic Rat Model with Hepatocellular Carcinoma. Mol Cancer Ther. 2017 Oct;16(10):2157-2165.

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