Reference Detail

Ref Type

Journal Article

PMID

(25700704)

Authors

Jalota-Badhwar A, Bhatia DR, Boreddy S, Joshi A, Venkatraman M, Desai N, Chaudhari S, Bose J, Kolla LS, Deore V, Yewalkar N, Kumar S, Sharma R, Damre A, More A, Sharma S, Agarwal VR

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	5	2015 May	1095-106	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Panulisib	Panulisib	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Panulisib		P7170\|AK15176	ALK Inhibitor 32 DNA_PK Inhibitor 9 mTOR Inhibitor 51 PI3K Inhibitor (Pan) 42	Panulisib (P7170) inhibits Pi3k, mTOR, Alk, and DNA-PK, resulting in inhibition of cancer cell growth (PMID: 25466244, PMID: 25700704).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA amp	ovarian cancer	sensitive	Panulisib	Preclinical	Actionable	In a preclinical study, Panulisib (P7170) downregulated mTOR pathway signaling in ovarian cancer cells with amplified PIK3CA (PMID: 25700704).	25700704
PTEN loss	prostate cancer	sensitive	Panulisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Panulisib (P7170) inhibited tumor growth in PTEN null prostate cancer cell xenograft models (PMID: 25700704).	25700704