Bhonde MR, Gupte RD, Dadarkar SD, Jadhav MG, Tannu AA, Bhatt P, Bhatia DR, Desai NK, Deore V, Yewalkar N, Vishwakarma RA, Sharma S, Kumar S, Dagia NM. A novel mTOR inhibitor is efficacious in a murine model of colitis.

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The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFb receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC 50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G 1 -S cellcycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies.

The PI3K/mTOR pathway plays an important role in regulating cancer cell proliferation, growth, survival and metabolism. Activation of the PI3K/mTOR pathway by multiple mechanisms is one of the most frequently observed defects in human malignancies. The objective of these studies was to identify a small molecule that has anti-angiogenic activity in addition to PI3K and mTOR activity. P7170, a novel small molecule, inhibits PI3Kα and mTOR enzyme activity with IC50 value of 2.2 nM and 4.4 nM respectively. P7170 also inhibits a number of PI3Kα mutants. The Inhibition of PI3K-mTOR pathway in different cancer cell lines was demonstrated by 80 to 100% inhibition of the expression of phosphorylated AKT (pAKT), S6 ribosomal protein (pS6), and 4EBP1 (p4EBP1) upon treatment with P7170 in a western blot assay. P7170 also inhibited ALK1, an important enzyme involved in angiogenesis, and DNA-PK, an enzyme involved in DNA repair with the IC50 values of 47 and 1.5 nM, respectively. P7170 exhibited potent cytotoxic activity with IC50 values ranging from 2 to 22 nM in a number of cancer cell lines eg. ovarian (A2780), prostate (PC3), triple negative breast (MDA-MB-231 and MDA-MB-468), ER positive breast (MCF7), hepatocellular (HuH-7), renal (786-O), pancreatic (Panc1, AsPC1, and BxPC3), and colon (HCT116, HCT115, SW480) cancer cell lines. More interestingly, P7170 inhibited pAKT and pS6 in stem-like cells isolated from tumor samples of colon, breast, and head and neck cancer patients. P7170 also inhibited anchorage independent colony formation of tumor cells isolated from 39 different human tumor xenografts derived from tumors of patients with different cancers. In addition, P7170 inhibited angiogenesis in vitro in a tube formation assay, and in a matrigel plug assay in animals. It also inhibited metastasis of breast cancer cells. P7170 demonstrated significant in vivo efficacy when administered orally in three human xenograft tumor models. Tumor growth inhibition of 79% at 15 mg/kg in prostate (PC3), 78% at 10 mg/kg in ovarian (A2780), and 64% at 10 mg/kg in triple negative breast (MDA-MB-231) xenografts. Conclusion: P7170 has a unique profile of PI3K-mTOR pathway inhibition along with anti-angiogenic and anti- DNA repair activities. Combined with its effect on stem-like cells, P7170 may prove to be an effective anti-cancer drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3742. doi:1538-7445.AM2012-3742

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Hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) are transcription factors and are activated in response to hypoxia. Both HIF-1α and STAT3 regulate various aspects of cancer biology such as cell survival, proliferation, angiogenesis etc. and are constitutively expressed in a wide range of human cancers. In the last decade, over expression of HIF-1α and STAT3 has been demonstrated in many common human cancers, thereby emerging as highly compelling anticancer targets for drug discovery. We herein report the design and synthesis of new imidazopyridine based potent dual inhibitors of HIF-1α and STAT3 pathways. The lead compound of this series P3971 has been identified as a potent inhibitor of HIF-1α (200 nM) and STAT3 (350 nM) with significant antiproliferative activity against various cancer cell lines. Moreover, P3971 was also found to be orally efficacious in HCT116 (colon cancer) and H460 (lung cancer) xenograft mice models.

<p>Supplementary Table S1; Supplementary Figures S1-S2. Supplementary Table 1. A) IC50 value of P7170 in pan-PI3K. B) Kinase inhibition data (ProQinase) of P7170 at 250 nM and 1. 5 μM.C) Kinase inhibition profile (KINOMEscan; 320 kinases) of P7170. D) IC50 values of selected kinases on treatment with P7170. Supplementary Figure S1. The growth response curves on treatment of P7170 on various patient-derived cancer cell lines. Supplementary Figure S2. P7170 induces autophagy in A2780 (A) and HCT116 (B) cells.</p>