Identification of Thieno[3,2‑<i>d</i>]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-d]­pyrimidine derivatives.
An intensive structure–activity relationship (SAR) study led
to the identification of 26 as a lead. Moreover, 26, a multitargeted kinase inhibitor, possesses excellent
potencies against FLT3 mutants as well as FAK. Gratifyingly, 26 remarkably inhibits recalcitrant FLT3 mutants, including
F691L, that cause drug resistance. Importantly, 26 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, 26 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, 26 remarkably
prevents metastasis of orthotopic tumors to lymph nodes. Taken together,
the results indicate that 26 possesses potential therapeutic
value against highly invasive cancers and relapsed AML.