Discovery of Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy

Abstract Epidermal growth factor receptor (EGFR) kinase inhibitors have revolutionized non-small cell lung cancer (NSCLC) treatment; however, the inevitable acquired resistance necessitates alternative strategies beyond conventional inhibition. Herein, we report the discovery and optimization of VHL-recruiting PROTAC degraders targeting the EGFR. Representative compounds C4 and D4 demonstrated potent, selective, and durable degradation of EGFRDel19 (C4: DC50 = 1.41 nM, Dmax = 99%; D4: DC50 = 9.14 nM, Dmax = 98%) and EGFRL858R (C4: DC50 = 3.30 nM, Dmax = 95%; D4: DC50 = 15.2 nM, Dmax = 98%). C4 induced cell cycle arrest and apoptosis, displayed subnanomolar antiproliferative activity, and drove significant tumor regression in an HCC827 xenograft model at low intravenous doses with a reduced twice-weekly schedule. Remarkably, D4 was orally bioavailable (F = 11.3%) and blood−brain barrier penetrant and completely inhibited tumor growth in vivo after oral dosing. Overall, this work provides promising starting points for next-generation EGFR-directed therapy.