Delving into the Latest Updates on Panulisib with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Mechanism

ALK1 inhibitors(Activin receptor-like kinase 1 inhibitors), Phosphatidylinositol 3-kinase family inhibitors, mTOR inhibitors(Serine/threonine-protein kinase mTOR inhibitors)

Therapeutic Areas

NeoplasmsRespiratory Diseases

Active Indication

KRAS mutant Non-small Cell Lung Cancer

Inactive Indication

Inflammation

Originator Organization

Piramal Phytocare Ltd.

Active Organization

Piramal Phytocare Ltd.

Inactive Organization

Piramal Enterprises Ltd.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure

Molecular FormulaC27H20F3N9

InChIKeyVJLRLTSXTLICIR-UHFFFAOYSA-N

CAS Registry1356033-60-7

Author: Kumar, Sanjay ; Sharma, Rajiv ; Venkatraman, Magesh ; Boreddy, Srinivas ; Yewalkar, Nilambari ; Deore, Vijaykumar ; Desai, Nikesh ; More, Avinash ; Chaudhari, Sarika ; Damre, Anagha ; Sharma, Somesh ; Bhatia, Dimple R. ; Joshi, Asavari ; Bose, Julie ; Agarwal, Veena R. ; Jalota-Badhwar, Archana ; Kolla, Lakshmi S.

AbstractThe 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. Mol Cancer Ther; 14(5); 1095–106. ©2015 AACR.

01 Jan 2015·Breast Cancer Research and TreatmentQ2 · MEDICINE

The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer

Q2 · MEDICINE

Article

Author: Vivian S. Chen ; Sarah R. Hosford ; Veena R. Agarwal ; Gary N. Schwartz ; Kevin Shee ; Lloye M. Dillon ; Jennifer R. Bean ; Kristen E. Muller ; Jonathan D. Marotti ; Kari M. Rosenkranz ; Todd W. Miller ; Lynn K. Symonds ; Philip Owens ; Richard J. Barth ; Wei Yang

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170. Fresh cores from primary ER+/HER2- tumors from two patients were treated ±P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤ 25 nM) and inhibited PI3K at higher concentrations (≥ 200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2- human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.

01 Dec 2014·Molecular CancerQ1 · MEDICINE

P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer

Q1 · MEDICINE

ArticleOA

Author: Anagha Damre ; Asavari Joshi ; Veena R Agarwal ; Julie Bose ; Prashant Tannu ; Prashant Kumar Pandey ; Venkatasubbaiah A Venkatesha ; Sanjay Kumar ; Sarika Choudhari ; Tausif Ahmed ; Vijaykumar Deore ; Dimple Bhatia ; Ramachandra Sangana ; Ankita Srivastava ; Magesh Venkataraman ; Vaibhavi J Lad ; Bichismita Sahu ; Somesh Sharma ; Vinay Sonawane

BACKGROUNDLung cancer is the major cause of cancer-related deaths and many cases of Non Small Cell Lung Cancer (NSCLC), a common type of lung cancer, have frequent genetic/oncogenic activation of EGFR, KRAS, PIK3CA, BRAF, and others that drive tumor growth. Some patients though initially respond, but later develop resistance to erlotinib/gefitinib with no option except for cytotoxic therapy. Therefore, development of novel targeted therapeutics is imperative to provide improved survival benefit for NSCLC patients. The mTOR cell survival pathway is activated in naïve, or in response to targeted therapies in NSCLC.METHODSWe have discovered P7170, a small molecule inhibitor of mTORC1/mTORC2/ALK1 and investigated its antitumor efficacy using various in vitro and in vivo models of human NSCLC.RESULTSP7170 inhibited the phosphorylation of AKT, S6 and 4EBP1 (substrates for mTORC2 and mTORC1) levels by 80-100% and growth of NSCLC cells. P7170 inhibited anchorage-independent colony formation of NSCLC patient tumor-derived cells subsistent of disease sub-types. The compound also induced apoptosis in NSCLC cell lines. P7170 at a well-tolerated daily dose of 20 mg/kg significantly inhibited the growth of NSCLC xenografts independent of different mutations (EGFR, KRAS, or PIK3CA) or sensitivity to erlotinib. Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed sub-micro molar tumor concentrations along with mTORC1/C2 inhibition.CONCLUSIONSOur results provide evidence of antitumor activity of P7170 in the erlotinib -sensitive and -insensitive models of NSCLC.

100 Deals associated with Panulisib

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	US	Piramal Enterprises Ltd.	01 Sep 2012
Solid tumor	Phase 1	IN	Piramal Enterprises Ltd.	01 Sep 2012
Inflammation	Phase 1	IN	Piramal Enterprises Ltd.	-
KRAS mutant Non-small Cell Lung Cancer	Preclinical	IN	Piramal Phytocare Ltd.	15 Apr 2012

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Phase 1 clinical trial (AACR2014)	Phase 1	Triple Negative Breast Cancer	-	P7170	tpckyuvqoa(ezwiujchwk) = shqdpnduro fblerojast (zgtvgxavpg )	Positive	01 Oct 2014