Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead Identification

TLDR

The study presents a library construction, in situ screening, and structure‑based drug design strategy that can be applied to identify leads for other kinases. The authors synthesized 350 furanopyrimidine compounds in parallel reactors, screened them in situ for Aurora and EGFR kinase activity, and validated binding modes with X‑ray co‑crystal structures. The optimized Aurora inhibitor 3 exhibited sub‑micromolar antiproliferative activity in HCT‑116 colon cancer cells, while the EGFR inhibitor 8 inhibited both wild‑type and mutant EGFR kinases and showed antiproliferative activity in HCC827 lung cancer cells.

Abstract

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.