Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug‐resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC‐01‐163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC‐01‐163 is also effective against osimertinib‐resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP‐site EGFR inhibitor, osimertinib, the anti‐proliferative activity of DDC‐01‐163 against L858R/T790M EGFR‐Ba/F3 cells is enhanced. Collectively, DDC‐01‐163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP‐site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.

中文翻译：

---

突变选择性变构 EGFR 降解剂可有效对抗多种耐药突变。

通过变构机制靶向表皮生长因子受体 (EGFR) 提供了一种潜在的治疗策略，以克服 ATP 结合位点内出现的耐药 EGFR 突变。在这里，我们开发了一种变构 EGFR 降解剂 DDC-01-163，它可以选择性抑制 L858R/T790M (L/T) 突变 Ba/F3 细胞的增殖，同时使野生型 EGFR Ba/F3 细胞不受影响。DDC-01-163 对具有 L/T/C797S 和 L/T/L718Q EGFR 突变的奥希替尼耐药细胞也有效。当与 ATP 位点 EGFR 抑制剂奥西替尼联合使用时，DDC-01-163 针对 L858R/T790M EGFR-Ba/F3 细胞的抗增殖活性增强。总的来说，DDC-01-163 是一种有前途的变构 EGFR 降解剂，作为单一药物以及与 ATP 位点抑制剂联合使用时，具有针对各种临床相关 EGFR 突变体的选择性活性。我们的数据表明，靶向蛋白质降解是一种有前途的突变 EGFR 药物开发方法。