Friday, May 1, 2015

Drugs in Clinical Pipeline: PND-1186

PND-1186 [2-((2-((2-methoxy-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)-N-methylbenzamide] is an ATP-competitive, reversible inhibitor of Focal Adhesion Kinase (FAK) activity with IC50 of 1.5 nM in vitro. PND-1186 has an IC50 of ~100 nM in breast carcinoma cells as determined by anti-phospho-specific immunoblotting to FAK Tyr-397.

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Tumor metastasis is a leading cause of cancer-related death.

PND-1186 did not alter c-Src or p130Cas tyrosine phosphorylation in adherent cells, yet functioned to restrain cell movement. Notably, 1.0 µM PND-1186 (5-fold above IC50) had limited effects on cell proliferation. However, under non-adherent conditions as spheroids and as colonies in soft agar, 0.1 µM PND-1186 blocked FAK and p130Cas tyrosine phosphorylation, promoted caspase-3 activation, and triggered cell apoptosis. PND-1186 inhibited 4T1 breast carcinoma subcutaneous tumor growth correlated with elevated tumor cell apoptosis and caspase 3 activation.

PND-1186 may function as a novel preventative and/or prophylactic anti-tumor agent.

The activity of PND-1186 is as follows:

IC50 (FAK enzyme assay) = 1.5 nM

IC50 (Inhibition of breast carcinoma cells) = ~ 100 nM

Common Name: PND-1186
Synonyms:  PND-1186; PND 1186; PND1186; SR 2516; SR-2516; SR2516; VS-4718; VS4718; VS 4718
IUPAC Name: 2-((2-((2-methoxy-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)-N-methylbenzamide
CAS Number: 1061353-68-1; 1356154-94-3 (hydrochloride); 1061353-69-2 (TFA)
Mechanism of Action: Kinase Inhibitor; FAK Inhibitor
Indication: Prophylactic Anti-tumor Agent
Development Stage: Investigational
Company: Verastem, Inc/ Poniard Pharmaceuticals Inc. (acquired by Allozyne Inc).

The selectivity of PND-1186 was evaluated using the Millipore KinaseProfiler Service. In this screen, 0.1 µM PND-1186 displayed specificity for FAK as well as Flt3 (FMS-like tyrosine kinase 3) kinase inhibition. At a higher PND-1186 concentration (1 µM), FAK and Flt3 had negligible activity and other kinases including ACK1 (activated Cdc42-associated tyrosine kinase 1), Aurora-A, CDK2 (cyclin-dependent kinase 2)/ cyclin A, insulin receptor (IR), Lck (lymphocyte-specific protein tyrosine kinase), and TrkA (tropomyosin-related kinase A) were inhibited greater than 50%. Flt3 expression is found in cells of hematopoietic origin and is not detectably expressed in 4T1, MDA-MB-231, or ID8 cells used herein [1].

Moreover, 0.1 µM PND-1186 is sufficient to promote 4T1 breast carcinoma and ID8 ovarian carcinoma cell apoptosis when grown under suspended, spheroid, or soft-agar conditions. This was associated with the inhibition of both FAK and p130Cas tyrosine phosphorylation, supporting the hypothesis that a FAK-p130Cas survival pathway facilitates three-dimensional (3D) cell growth. PND-1186 inhibits 4T1 subcutaneous tumor growth and is associated with tumor cell apoptosis. Similarly, low-dose drinking water administration of PND-1186 inhibited ID8 ovarian ascites-associated tumor burden without murine weight loss or morbidity.

FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs [2]. 

Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression [2].


1. Tanjoni, I.; et. al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer Biol Ther 2010, 9(10), 764-777.
2. Walsh, C.; et. al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer Biol Ther 2010, 9(10), 778-90.