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 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.

Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors

“…Other approaches to inhibit ALK1 signaling are via small molecules or neutralizing antibodies (39,40). One of these antibodies, PF-03446962, currently under phase II clinical development, inhibits binding of BMP9 to ALK1 and prevents BMP9-induced recruitment of the coreceptor endoglin into the signaling complex (41,42).…”

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

“…Matrigel-based tube formation [47] was used to evaluate the ability of endothelial cells to form capillary-like structures. In brief, 24-well plates were coated with Growth Factor-Reduced Basement Membrane Matrix (50 μL/cm 2 ) at 37°C for 30 minutes.…”

“…The assay was conducted as described previously [47]. C57BL/6J mice at 6 weeks of age were purchased from Charles River Laboratories and divided into three groups, PBS, BMP9, and BMP9 with metformin treatment, each containing 4 mice.…”

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

“…This quinoline compounds demonstrated potent inhibition activity on mTORC1/mTORC2/ALK1, cell cycle arrest, induction of apoptosis, antiangiogenic activity. Moreover, it showed antitumor efficacy on both in vitro and in vivo studies against the erlotinib–sensitive and –insensitive models NSCLC and anti-estrogen models of ER+ breast cancer [ 86 , 87 , 88 ], reaching the clinical trials evaluation for patients with advanced refractory solid tumours ( number NCT01762410) [ 89 ].…”