Abstract A86: Design, synthesis, and SAR of focal adhesion kinase (FAK) inhibitors

Focal adhesion kinase (FAK) is a non‐tyrosine kinase that localizes to focal adhesion plaques. It is activated in response to intergin binding to cellular ligands and when phosphorylated inhibits anoikis allowing for anchorage independent cell growth. Recent studies have shown increased FAK expression and phosphorylation status in many types of invasive and aggressive human tumors strongly suggesting FAK is a possible target for anticancer chemotherapy. Literature, in house HTS and de novo studies identified 2, 4‐diaminopyrimidines as potent FAK inhibitors. Early SAR efforts quickly determined that smaller substituents, particularly CF3, were optimal in the C5 position. Parallel medicinal chemistry strategies were executed for the C2 and C4 positions. These studies suggested that substituted aryl and fused heteroaryl groups at the C2 position in conjunction with substituted phenyl and heterocycles at the C4 position imparted optimum activity and metabolic stability. Inhibitor‐FAK co‐crystal structures were utilized to guide in the SAR strategy around the 2, 4‐diaminopyrimidine template which afforded several lead compounds. The team9s effort culminated in the advancement of PF‐562,271 as a potent and reversible inhibitor of FAK (kinase IC50 of 2 nM and cell IC50 of 5 nM) that is > 100x selective against a long list of non‐target kinases. In summary, detailed SAR studies were executed on the 2, 4‐diaminopyrimidine templates that produced potent inhibitors of FAK with improved ADME properties, and identified a novel and potent series of FAK inhibitors that are selective against most other kinases and have shown activity in clinical trials. This poster will present design, synthesis, challenging chemistry, optimization, and complete inhibitor chemical structures of lead analogs. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A86.