Abstract 5608: Design and discovery of BH-30643: A novel, reversible, mutant-selective macrocyclic EGFR inhibitor invulnerable to common resistance mutations
Authors: J. Jean Cui, Eugene Rui, Evan Rogers, Dayong Zhai, Ping Jiang, Zhenping Wang, Yue Hu, Nancy Ling, Danan Li, Joshua Choi, Anindya Sarkar, Levan Darjania, Zhengwei Peng, Wei Deng
Journal: Cancer Research (2025)

Abstract Outcomes on tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC fall short of the durable benefit observed with next-generation targeted therapies in ALK and ROS1-driven NSCLC. We reviewed the chemical structures of 30+ existing EGFR TKIs in pursuit of a novel chemical scaffold that could offer a more durable treatment response. First-generation (1G) (e.g. gefitinib) and second-generation (2G) (e.g. afatinib) EGFR TKIs share an anilinoquinazoline scaffold which is vulnerable to T790M gatekeeper resistance. Third-generation (3G) (e.g. osimertinib) EGFR TKIs employ a less potent pyrimidine scaffold and obtain good potency including T790M through introduction of an irreversible binding at C797. However, the dependence of 3G EGFR TKIs on irreversible binding renders these agents vulnerable to C797S resistance. The established EGFR TKI scaffolds additionally have more limited potency against a growing family of non-classic EGFR mutations (atypical and ex20ins). To increase the breadth and durability of EGFR TKIs in EGFR mutant NSCLC, we have designed a novel reversible macrocyclic scaffold that fully leverages the characteristics of EGFR active conformation and introduces novel and precise interactions with mutant EGFRs via a three-dimensional macrocyclic structure. Our efforts led to the discovery of BH-30643, a potent, orally bioavailable, reversible, ATP-competitive macrocyclic inhibitor selective for mutant EGFRs. BH-30643 demonstrates potent anti-cell proliferation activity against classical mutations (IC50: ex19del 0.73 nM and L858R 0.18 nM), with &amp;gt;250-fold selectivity over wildtype (WT) EGFR (IC50: 191.5 nM). It additionally exhibits ∼50-fold selectivity compared to WT HER2 (IC50: 42.2 nM), in contrast to the 2G and 3G EGFR TKIs with limited selectivity over WT HER2, which may contribute to diarrhea as a side effect. The potency of BH-30643 is maintained in the presence of T790M (IC50: ex19del/T790M 0.43 nM and L858R/T790M 0.69 nM), C797S (IC50: ex19del/C797S 0.05 nM and L858R/C797S 0.10 nM) or both (IC50: ex19del/T790M/C797S 0.43 nM and L858R/T790M/C797S 0.54 nM). Potency is additionally evident across a breadth of EGFR mutations including atypical mutations (IC50: 0.05-8.84 nM), and ex20ins mutations (IC50: 1.74-64.68 nM). BH-30643 also showed potent activity against mutant HER2s (IC50: 3.25-18.8 nM), especially in the presence of T780M or C805S resistance mutation. Moreover, BH-30643 showed great selectivity in screens against 372 WT human kinases and 87 safety-related targets. The unique profile of BH-30643 offers a promising strategy to target a range of classical and non-classical EGFR activating mutations without vulnerability to common on-target resistance mutations. Such an "OMNI-EGFRTM" inhibitor may represent a new generation of EGFR TKIs with potential to overcome some of the limitations of earlier agents. Citation Format: J. Jean Cui, Eugene Rui, Evan Rogers, Dayong Zhai, Ping Jiang, Zhenping Wang, Yue Hu, Nancy Ling, Danan Li, Joshua Choi, Anindya Sarkar, Levan Darjania, Zhengwei Peng, Wei Deng. Design and discovery of BH-30643: A novel, reversible, mutant-selective macrocyclic EGFR inhibitor invulnerable to common resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5608.