PND-1186

Short Summary : Potent FAK inhibitor

Category : Tyrosine Kinase|FAK

Purity : 0.9988

CAS Number : 1061353-68-1

Formula : C25H26F3N5O3

Molecular Weight : 501.5

SMILE : CNC(C1=C(NC2=CC(NC3=CC=C(N4CCOCC4)C=C3OC)=NC=C2C(F)(F)F)C=CC=C1)=O

Solubility : >25.1mg/mL in DMSO

Storage : Store at -20°C

Description : PND-1186 is a reversible inhibitor of FAK (focal adhesion kinase) with IC50 value of 1.5 nM [1].The cytoplasmic protein-tyrosine kinase FAK is associated with integrins and growth factor receptors. It modulates a variety of cellular processes when it is activated. Since the elevated expression of FAK is found in many tumors, the inhibitors of FAK are developed as anti-tumor drugs in cancer therapy. PND-1186 is one of these ATP-competitive small-molecule inhibitors. It inhibited the autophosphorylation of FAK tyrosine-397 with IC50 value of 0.1 ?M in breast carcinoma cells. When the concentration was up to 1 ?M, PND-1186 also inhibited more than 50% of the activities of other kinases, such as CDK2, Lck, Aurora-A and ACK1 [1].PND-1186 at concentrations of 0.1 to 1 ?M inhibited the phosphorylation of FAK Tyr-397 and increased the protein level of FAK in murine breast carcinoma 4T1 cells, ID8 ovarian carcinoma cells and human MD-MBA-231 cells. Meanwhile, PND-1186 significantly induced cell apoptosis and increased the cleavage caspase 3 in suspended but not adherent 4T1 cells. Besides that, PND-1186 is found to inhibit the movement of 4T1 cells in both the wound healing assays and the millicell chamber motility assays. Treatment of PND-1186 at 0.4 ?M for 4 hours showed the maximal inhibition of about 60%. In HEY ovarian cancer cells, treatment of PND-1186 caused the decrease of pY397 FAK, ?5 integrin and osteopontin. It also induced cell cycle arrest at G0-G1 phase [1, 2].In subcutaneous 4T1 tumors, administration of PND-1186 at dose of 100 mg/kg caused inhibition of both FAK Tyr-397 phosphorylation and p130Cas Tyr-410 phosphorylation. In orthotopic 4T1 tumors, administration of 150 mg/kg PND-1186 for 16 days finally reduced 3.1-fold tumor volume. Moreover, PND-1186 is reported to have anti-inflammatory effects and can suppress the processes of spontaneous breast cancer metastasis to lung [3].References:1.Tanjoni I, Walsh C, Uryu S, et al. PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer biology & therapy, 2010, 9(10): 764-777.2.Tancioni I, Uryu S, Sulzmaier F J, et al. FAK inhibition disrupts a beta5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Molecular Cancer Therapeutics, 2014: molcanther. 1063.2014.3.Walsh C, Tanjoni I, Uryu S, et al. Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer biology & therapy, 2010, 9(10): 778.

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