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

Abstract

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-<i>d</i>]pyrimidine derivatives. An intensive structure-activity relationship (SAR) study led to the identification of <b>26</b> as a lead. Moreover, <b>26</b>, a multitargeted kinase inhibitor, possesses excellent potencies against FLT3 mutants as well as FAK. Gratifyingly, <b>26</b> remarkably inhibits recalcitrant FLT3 mutants, including F691L, that cause drug resistance. Importantly, <b>26</b> 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, <b>26</b> 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, <b>26</b> remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that <b>26</b> possesses potential therapeutic value against highly invasive cancers and relapsed AML.