OSI-027

• CAT Number: I005567
• CAS Number: 936890-98-1
• Molecular Formula: C₂₁H₂₂N₆O₃
• Molecular Weight: 406.44
• Purity: ≥95%
• Target: mTOR
• Solubility: DMSO ≥78mg/mL Water <1.2mg/mL Ethanol <1.2mg/mL
• Storage: 3 years -20C powder
• IC50: 22/65 nM (mTORC1/2)
• IUPAC Name: 4-[(5Z)-4-amino-5-(7-methoxyindol-2-ylidene)-1H-imidazo[5,1-f][1,2,4]triazin-7-yl]cyclohexane-1-carboxylic acid
• InChI: InChI=1S/C21H22N6O3/c1-30-15-4-2-3-13-9-14(25-16(13)15)17-18-19(22)23-10-24-27(18)20(26-17)11-5-7-12(8-6-11)21(28)29/h2-4,9-12H,5-8,22H2,1H3,(H,23,24)(H,28,29)/b17-14-
• InChIKey: CDNMDRUIGNHEMR-VKAVYKQESA-N
• SMILES: COC1=CC=CC2=CC(=C3C4=C(N=CNN4C(=N3)C5CCC(CC5)C(=O)O)N)N=C21

OSI-027 (CAT: I005567) is a potent and selective inhibitor of both mTORC1 and mTORC2. It exhibits an IC50 of 22 nM for mTORC1 and 65 nM for mTORC2, with over 100-fold selectivity for mTOR compared to PI3Kα, PI3Kβ, PI3Kγ, or DNA-PK. OSI-027 demonstrates anti-proliferative activity against various acute leukemia cell lines of myeloid/megakaryocytic origin, including U937, KG-1, KBM-3B, ML-1, HL-60, and MEG-01 cells, in a dose-dependent manner. In breast cancer cells, inhibition of mTORC1/2 by OSI-027 effectively suppresses the phosphorylation of Akt (S473) and inhibits cell proliferation. OSI-027 shows promise as a potential therapeutic agent for cancer treatment, particularly in leukemia and breast cancer.

Overview of Clinical Research

Originator: OSI Pharmaceuticals
Class: 2 ring heterocyclic compounds; Antineoplastics; Carboxylic acids; Imidazoles; Indoles; Pyrazines; Small molecules; Triazines
Mechanism of Action: MTORC1 protein inhibitors; MTORC2 protein inhibitors
Orphan Drug Status: No

Reference

1. DNA Cell Biol. 2015 Oct;34(10):610-7. doi: 10.1089/dna.2015.2886. Epub 2015 Aug 18.
The Antipancreatic Cancer Activity of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2.
Chen B(1), Xu M(1), Zhang H(1), Xu MZ(2), Wang XJ(1), Tang QH(1), Tang JY(2).
Author information:
(1)1 Department of Biliary and Pancreatic Surgery, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China . (2)2 Department of Emergency, East Hospital Affiliated to Tongji University in Shanghai , Shanghai, China .
In the present study, we investigated the potential activity of OSI-027, a potent and selective mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells both in vitro and in vivo. We demonstrated that OSI-027 inhibited survival and growth of both primary and transformed (PANC-1 and MIA PaCa-2 lines) human pancreatic cancer cells. Meanwhile, OSI-027 induced caspase-dependent apoptotic death of the pancreatic cancer cells. On the other hand, caspase inhibitors alleviated cytotoxicity by OSI-027. At the molecular level, OSI-027 treatment blocked mTORC1 and mTORC2 activation simultaneously, without affecting ERK-mitogen-activated protein kinase activation. Importantly, OSI-027 activated cytoprotective autophagy in the above cancer cells. Whereas pharmacological blockage of autophagy or siRNA knockdown of Beclin-1 significantly enhanced the OSI-027-induced activity against pancreatic cancer cells. Specifically, a relatively low dose of OSI-027 sensitized gemcitabine-induced pancreatic cancer cell death in vitro. Further, administration of OSI-027 or together with gemcitabine dramatically inhibited PANC-1 xenograft growth in severe combined immunodeficiency mice, leading to significant mice survival improvement. In summary, the preclinical results of this study suggest that targeting mTORC1/2 synchronously by OSI-027 could be further investigated as a valuable treatment for pancreatic cancer.
2. Mol Cancer Ther. 2011 Aug;10(8):1394-406. doi: 10.1158/1535-7163.MCT-10-1099. Epub 2011 Jun 14.
Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin.
Bhagwat SV(1), Gokhale PC, Crew AP, Cooke A, Yao Y, Mantis C, Kahler J, Workman J, Bittner M, Dudkin L, Epstein DM, Gibson NW, Wild R, Arnold LD, Houghton PJ, Pachter JA.
Author information:
(1)Cancer Biology, OSI Pharmaceuticals Inc., Farmingdale, NY 11735, USA.
The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC(50) values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kα, PI3Kβ, PI3Kγ, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. OSI-027 shows concentration-dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI-027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients.