Identification of Thieno[3,2- d ]pyrimidine Derivatives as Dual Inhibitors of Focal Adhesion Kinase and FMS-like Tyrosine Kinase 3

Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno[3,2- ]pyrimidine derivatives. An intensive structure-activity relationship (SAR) study led to the identification of as a lead. Moreover, , a multitargeted kinase inhibitor, possesses excellent potencies against FLT3 mutants as well as FAK. Gratifyingly, remarkably inhibits recalcitrant FLT3 mutants, including F691L, that cause drug resistance. Importantly, is superior to PF-562271 in terms of apoptosis induction, anchorage-independent growth inhibition, and tumor burden reduction in the MDA-MB-231 xenograft mouse model. Also, causes regression of tumor growth in the MV4-11 xenograft mouse model, indicating that it could be effective against acute myeloid leukemia (AML). Finally, in an orthotopic mouse model using MDA-MB-231, remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that possesses potential therapeutic value against highly invasive cancers and relapsed AML.