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MedKoo CAT#: 200281
CAS#: 1313881-70-7 (free base)
Description: Miransertib, also known as ARQ 092, is an oral activie, potent and selective AKT inhibitor with IC50 values: 5.0 nM (AKT1); 4.5 nM (AKT2); 16 nM (AKT3). ARQ 092 binds to and inhibits the activity of AKT in a non-ATP competitive manner, which may result in the inhibition of the PI3K/AKT signaling pathway. This may lead to the reduction in tumor cell proliferation and the induction of tumor cell apoptosis. ARQ-092 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. ARQ-092 also served as a potent inhibitor of the AKT1-E17K mutant protein and inhibited tumor growth in a human xenograft mouse model of endometrial adenocarcinoma.
MedKoo Cat#: 200281
CAS#: 1313881-70-7 (free base)
Chemical Formula: C27H24N6
Exact Mass: 432.2062
Molecular Weight: 432.531
Elemental Analysis: C, 74.98; H, 5.59; N, 19.43
Related CAS #: 1313881-70-7 (free) 1313883-00-9 (HCl) 1817727-87-9 (3HCl)
Synonym: ARQ092; ARQ-092; ARQ 092; Miransertib
IUPAC/Chemical Name: 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
InChi Key: HNFMVVHMKGFCMB-UHFFFAOYSA-N
InChi Code: InChI=1S/C27H24N6/c28-24-21(8-4-17-30-24)25-32-23-14-13-22(18-6-2-1-3-7-18)31-26(23)33(25)20-11-9-19(10-12-20)27(29)15-5-16-27/h1-4,6-14,17H,5,15-16,29H2,(H2,28,30)
SMILES Code: NC1=NC=CC=C1C2=NC3=CC=C(C4=CC=CC=C4)N=C3N2C5=CC=C(C6(N)CCC6)C=C5
1313881-70-7 (ARQ-092 free)
1313883-00-9 (ARQ-092 HCl)
1817727-87-9 (ARQ-092 3HCl).
ARQ 092 was identified through this screening paradigm following in vitro and in vivo optimization and was selected for further development. Crystallographic studies provided evidence that this mechanism of inhibition of AKT had been achieved. ARQ 092 binds to inactive, unphosphorylated AKT1 with sub-nanomolar affinity (Kd = 0.28 nM measured by surface plasma resonance) and biochemically inhibits all three isoforms (IC50 values of 3 nM, 4.5 nM, and 5.5 nM respectively for AKT1, AKT2, and AKT3). ARQ 092 displayed inhibition kinetics against AKT1 which were not affected by ATP concentrations up to 1000 M. When screened against a panel of over 300 kinases, ARQ 092 inhibited only three kinases within 100-fold of its IC50 against AKT1. ARQ 092 potently inhibited AKT phosphorylation (Ser473 & Thr308) in AN3CA human endometrial carcinoma cells (EC50 values of 39 nM and 61 nM, respectively for p-Ser473 & p-Thr308) and demonstrated concentration-dependent inhibition of phosphorylation of the downstream AKT substrate PRAS40. ARQ 092 inhibited growth of AN3CA cells (GI50 = 555 nM), A2780 cells (GI50 = 400 nM), and IGROV-1 cells (GI50 = 66 nM), in addition to LNCaP, ZR-75Â–1, and BT-474 human cancer cell lines (GI50 values ranging from 1 to 4 μM). Following a single oral dose of ARQ 092, inhibition of AKT and PRAS40 phosphorylation was documented in vivo in both AN3CA human endometrial tumor and BT474 human breast tumor xenograft models. The growth of AN3CA tumor xenografts was markedly suppressed after daily oral administration of ARQ 092 for 10 days. Finally, ARQ 092 was shown to have good pharmaceutical properties and was advanced into preclinical development. (source: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A230. ).
1: 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
-2-amine (ARQ 092): An Orally Bioavailable, Selective, and Potent Allosteric AKT
Inhibitor. J Med Chem. 2016 Jun 29. [Epub ahead of print] PubMed PMID: 27305487.
2: Lindhurst MJ, Yourick MR, Yu Y, Savage RE, Ferrari D, Biesecker LG. Repression
of AKT signaling by ARQ 092 in cells and tissues from patients with Proteus
syndrome. Sci Rep. 2015 Dec 11;5:17162. doi: 10.1038/srep17162. PubMed PMID:
26657992; PubMed Central PMCID: PMC4675973.
3: Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, Hall T, Abbadessa G, Schwartz
B. Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor,
ARQ 092. PLoS One. 2015 Oct 15;10(10):e0140479. doi:
10.1371/journal.pone.0140479. eCollection 2015. PubMed PMID: 26469692; PubMed
Central PMCID: PMC4607407.