Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models
Colin Walsh 1, Isabelle Tanjoni, Sean Uryu, Alok Tomar, Ju-Ock Nam, Hong Luo, Angelica Phillips, Neela Patel, Cheni Kwok, Gerald McMahon, Dwayne G Stupack, David D Schlaepfer

Tumor metastasis is really a leading reason for cancer-related dying. Focal adhesion kinase (FAK) is really a cytoplasmic tyrosine kinase employed to integrin-mediated matrix attachment sites where FAK activity is implicated within the charge of cell survival, migration, and invasion. Although genetic studies support the significance of FAK activity to promote tumor progression, it remains unclear whether medicinal FAK inhibition prevents tumor metastasis. Here, we reveal that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor effectiveness in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) demonstrated promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hrs. Dental administration of 150 mg/kg PND-1186 gave a far more sustained PK profile verses i.p., so when given two times daily, PND-1186 considerably inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lung area. Furthermore, low-level .5 mg/ml PND-1186 ad libitum administration in consuming water avoided 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 wasn’t cytotoxic to cells in adherent culture, tumors from creatures receiving PND-1186 exhibited elevated TUNEL staining, decreased leukocyte infiltrate and reduced tumor-connected 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 tumor and stromal cells. As dental administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be helpful clinically to curb breast tumor progression.VS-4718