P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity.

Abstract

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 TGFβ 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 (IC50 < 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 G1-S cell-cycle 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.

• Authors: Archana Jalota-Badhwar, Dimple R Bhatia, Srinivas Boreddy, Asavari Joshi, Magesh Venkatraman, Nikesh Desai, Sarika Chaudhari, Julie Bose, Lakshmi S Kolla, Vijaykumar Deore, Nilambari Yewalkar, Sanjay Kumar, Rajiv Sharma, Anagha Damre, Avinash More, Somesh Sharma, Veena R Agarwal
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 5 Pg. 1095-106 (May 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25700704 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Imidazoles
• P7170 compound
• Quinolines
• TOR Serine-Threonine Kinases
• ACVRL1 protein, human
• Activin Receptors, Type II

Topics

• Activin Receptors, Type II (antagonists & inhibitors)
• Administration, Oral
• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Aorta, Thoracic (cytology, drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Hep G2 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Imidazoles (administration & dosage, pharmacology)
• Male
• Mice
• Prostatic Neoplasms (drug therapy, metabolism)
• Quinolines (administration & dosage, pharmacology)
• Rats
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Xenograft Model Antitumor Assays