WARNING: This product is for research use only, not for human or veterinary use.
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
Name: Miransertib free base
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
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
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||Masupirdine free base (SUVN-502 free base) is a potent, selective, orally bioavailable, and brain penetrant 5-HT6 receptor antagonist (Ki of 2.04 nM for human 5-HT6 receptor).|
|In vitro activity:||To determine the inhibitory effect of Miransertib on Leishmania growth, its effect on promastigotes of L. amazonensis and L. donovani was studied. First, promastigotes of L. amazonensis were treated with various concentrations of Miransertib for 24 hours. The number of viable parasites was determined by MTT assays. Fig 1 shows that increasing concentrations of Miransertib results in death of Leishmania parasites. The EC50 of Miransertib on L. amazonensis was estimated at 7.87 ± 0.93 μM (Fig 1A). For comparison, the EC50 of miltefosine on L. amazonensis was estimated at 40.83 ± 5.03 μM. The efficacy of Miransertib on L. donovani parasites was also determined to be 12.75 ± 1.14μM which was similar to the EC50 of miltefosine on L. donovani, which was 10.54 ± 3.51 μM (Fig 1B). These results show that Miransertib is as effective as miltefosine in killing L. donovani promastigotes, but it is slightly more effective on L. amazonensis promastigotes as compared to miltefosine. Reference: PLoS One. 2018 Nov 6;13(11):e0206920. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30399177/|
|In vivo activity:||For in vivo efficacy of Miransertib, groups of L. donovani infected BALB/c mice (seven days post infection with stationary phase promastigotes) were dosed daily, for five consecutive days per week with an oral formulation of Miransertib (50 and 75 mg/kg). On day 28 post-infection, the parasite burdens in the livers and spleens of infected mice were quantified. The only available FDA approved oral anti-leishmanial drug miltefosine (20 mg/kg, once daily, 5 days per week) was included as a positive control. Both Miransertib and miltefosine were well tolerated at both doses throughout the study, with no mice displaying any overt signs of toxicity. The results show that Miransertib effectively suppressed parasite burdens by 80–90% (Fig 3A and 3B). In fact, at 50 and 75 mg/kg, Miransertib effectively cured 50% of the study mice (2/4 mice in both treatment groups), with no detectable parasites in the livers and spleens. 50 and 75 mg/kg doses of Miransertib compared favorably with miltefosine in the spleen (Fig 3A), whereas it was more active than miltefosine in the liver (Fig 3B). These results show that Miransertib has potent anti-leishmanial activity in vivo against L. donovani. Reference: PLoS One. 2018 Nov 6;13(11):e0206920. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30399177/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 432.531 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Nandan D, Zhang N, Yu Y, Schwartz B, Chen S, Kima PE, Reiner NE. Miransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania. PLoS One. 2018 Nov 6;13(11):e0206920. doi: 10.1371/journal.pone.0206920. PMID: 30399177; PMCID: PMC6219794.|
|In vivo protocol:||1. Nandan D, Zhang N, Yu Y, Schwartz B, Chen S, Kima PE, Reiner NE. Miransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania. PLoS One. 2018 Nov 6;13(11):e0206920. doi: 10.1371/journal.pone.0206920. PMID: 30399177; PMCID: PMC6219794.|
1: Nandan D, Zhang N, Yu Y, Schwartz B, Chen S, Kima PE, Reiner NE. Miransertib (ARQ 092), an orally-available, selective Akt inhibitor is effective against Leishmania. PLoS One. 2018 Nov 6;13(11):e0206920. doi: 10.1371/journal.pone.0206920. eCollection 2018. PubMed PMID: 30399177; PubMed Central PMCID: PMC6219794.
2: Bastian C, Quinn J, Tripathi A, Aquila D, McCray A, Dutta R, Baltan S, Brunet S. CK2 inhibition confers functional protection to young and aging axons against ischemia by differentially regulating the CDK5 and AKT signaling pathways. Neurobiol Dis. 2018 Jun 23. pii: S0969-9961(18)30149-9. doi: 10.1016/j.nbd.2018.05.011. [Epub ahead of print] PubMed PMID: 29944965.
3: Ranieri C, Di Tommaso S, Loconte DC, Grossi V, Sanese P, Bagnulo R, Susca FC, Forte G, Peserico A, De Luisi A, Bartuli A, Selicorni A, Melis D, Lerone M, Praticò AD, Abbadessa G, Yu Y, Schwartz B, Ruggieri M, Simone C, Resta N. In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS). Neurogenetics. 2018 May;19(2):77-91. doi: 10.1007/s10048-018-0540-1. Epub 2018 Mar 16. PubMed PMID: 29549527; PubMed Central PMCID: PMC5956072.
4: Jilkova ZM, Kuyucu AZ, Kurma K, Ahmad Pour ST, Roth GS, Abbadessa G, Yu Y, Schwartz B, Sturm N, Marche PN, Hainaut P, Decaens T. Combination of AKT inhibitor ARQ 092 and sorafenib potentiates inhibition of tumor progression in cirrhotic rat model of hepatocellular carcinoma. Oncotarget. 2018 Jan 23;9(13):11145-11158. doi: 10.18632/oncotarget.24298. eCollection 2018 Feb 16. PubMed PMID: 29541403; PubMed Central PMCID: PMC5834253.
5: Wang J, Chandrasekhar V, Abbadessa G, Yu Y, Schwartz B, Kontaridis MI. In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy. PLoS One. 2017 Jun 5;12(6):e0178905. doi: 10.1371/journal.pone.0178905. eCollection 2017. PubMed PMID: 28582432; PubMed Central PMCID: PMC5459472.
6: 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. doi: 10.1158/1535-7163.MCT-16-0602-T. Epub 2017 May 31. PubMed PMID: 28566435.
7: Yu Y, Hall T, Eathiraj S, Wick MJ, Schwartz B, Abbadessa G. 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. doi: 10.1097/CAD.0000000000000486. PubMed PMID: 28240679; PubMed Central PMCID: PMC5404396.
8: 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. doi: 10.3324/haematol.2016.151159. Epub 2016 Oct 6. PubMed PMID: 27758820; PubMed Central PMCID: PMC5286933.
9: 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. doi: 10.1021/acs.jmedchem.6b00619. Epub 2016 Jun 29. PubMed PMID: 27305487.
10: 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.
11: 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.
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. ).