Design, Synthesis, and Evaluation of ()-8-((Tetrahydrofuran-2-yl)methyl)pyrido[2,3-]pyrimidin-7-ones as Novel Selective ACK1 Inhibitors to Combat Acquired Resistance to the Third-Generation EGFR Inhibitor.

Activated Cdc42-associated kinase 1 (ACK1) alterations have been considered to mediate bypass acquired resistance to the third-generation EGFR inhibitors (ASK120067 and osimertinib) in NSCLC. Despite many efforts to develop ACK1 small molecule inhibitors, no selective inhibitors have entered clinical trials. We used structure-based drug design to obtain a series of ()-8-((tetrahydrofuran-2-yl)methyl)pyrido [2,3-]pyrimidin-7-ones as novel selective ACK1 inhibitors. One of the representative compounds, , potently inhibited ACK1 kinase with an IC of 2.1 nM while sparing SRC kinase (IC = 218.7 nM). Further, displayed good kinome selectivity in a profiling of 468 kinases. In the ASK120067-resistant lung cancer cell line (67R), dose-dependently inhibited the phosphorylation of ACK1 and downstream AKT pathway and showed a strong synergistic anti-tumor effect in combination with ASK120067 in vitro. Additionally, also exhibited reasonable PK profiles with an oral bioavailability of 19.8% at the dose of 10 mg/kg, which provided a promising lead for further development of new anticancer drugs.