HBE-843, a Novel, Potent, and Selective EGFR Targeting PROTAC for the Treatment of Non-Small-Cell Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The EGFR C797S mutation confers resistance to third-generation EGFR-tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC).
• Targeting mutant EGFR while sparing wild-type EGFR is crucial for effective NSCLC treatment.

Purpose of the Study:

• To develop and characterize a novel, selective EGFR PROTAC (HBE-843) capable of degrading mutant EGFR, including the C797S resistance mutation.
• To evaluate the efficacy and mechanism of HBE-843 in preclinical NSCLC models.

Main Methods:

• Synthesis and characterization of HBE-843, a novel EGFR PROTAC.
• In vitro assessment of HBE-843's degradation activity against various EGFR mutations (L858R, exon 19 deletion, T790M, C797S) and wild-type EGFR.
• Determination of GI50, DC50, and Dmax values.
• Mechanistic studies involving the CRBN-associated proteasome pathway and ERK signaling.
• In vivo efficacy studies in L858R-induced NSCLC xenografts.

Main Results:

• HBE-843 demonstrated potent degradation of EGFR mutants (L858R, exon 19 deletion, T790M, C797S) with low nanomolar GI50 values (26-103 nM), while sparing wild-type EGFR.
• HBE-843 achieved dose-dependent reduction in EGFR protein levels in mutant cells (DC50: 1.9-18 nM, Dmax >90%).
• Degradation occurred via the CRBN-proteasome pathway, inhibiting ERK signaling and cell growth.
• In vivo studies showed 112% tumor growth inhibition in L858R-induced NSCLC models.

Conclusions:

• HBE-843 is a highly selective EGFR degrader with potent activity against clinically relevant EGFR mutations, including C797S.
• HBE-843 effectively overcomes resistance mediated by EGFR mutations through proteasomal degradation.
• HBE-843 shows significant preclinical efficacy and represents a promising lead compound for developing new therapies for NSCLC.