Potent dual EGFR/Her4 tyrosine kinase inhibitors containing novel (1,2-dithiolan-4-yl)acetamides

Bioorganic & Medicinal Chemistry Letters
2020.0

Abstract

Modifications at C<sub>6</sub> and C<sub>7</sub> positions of 3-cyanoquinolines 6 and 7 led to potent inhibitors of the ErbB family of kinases particularly against EGFR<sup>WT</sup> and Her4 enzymes in the radioisotope filter binding assay. The lead (4, SAB402) displayed potent dual biochemical activities with EGFR<sup>WT</sup>/Her4 IC<sub>50</sub> ratio of 80 due to its potent inhibition of Her4 activity (IC<sub>50</sub> 0.03 nM), however, the selectivity towards activating mutations (EGFR<sup>L858R</sup>, EGFR<sup>ex19del</sup>) was decreased. Inhibitor 4 also exhibited excellent growth inhibition in seven different cancer types and reduced cell viability in female NMRI nude mice in the intraperitoneally implanted hollow fibers which have been loaded with MOLT-4 (leukemia) and NCI-H460 (NSCLC) cells in a statistically significant manner.

DOI： 10.1016/j.bmcl.2020.127288

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