title: 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.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Jalota-Badhwar
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Dimple R
authors.initials: DR
authors.lastname: Bhatia
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Boreddy
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Asavari
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Magesh
authors.initials: M
authors.lastname: Venkatraman
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Nikesh
authors.initials: N
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Chaudhari
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Julie
authors.initials: J
authors.lastname: Bose
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Kolla
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Deore
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Nilambari
authors.initials: N
authors.lastname: Yewalkar
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Anagha
authors.initials: A
authors.lastname: Damre
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Avinash
authors.initials: A
authors.lastname: More
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India.
authors.forename: Somesh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, Piramal Enterprises Ltd., Mumbai, India. Veena_828@yahoo.com.
authors.forename: Veena R
authors.initials: VR
authors.lastname: Agarwal
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007093:Imidazoles; C000601501:P7170 compound; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II