BH-30643：一种新型大环非共价、突变体选择性EGFR抑制剂，解决当代EGFR TKI在耐药性和效力上的局限

Historical design of EGFR tyrosine kinase inhibitors (TKIs) left them vulnerable to recurrent resistance liabilities which curtail the durability of their clinical effect. These TKIs gain potency either by binding the EGFR kinase back pocket or by forming covalent bond with C797, rendering them susceptible to T790M or C797S resistance mutations. Limited potency or PK exposure of some TKIs also permits regrowth of residual tumor cells and thereby shortening their duration of clinical benefit. BH-30643 was designed as a macrocyclic, non-covalent, mutant selective OMNI-EGFR inhibitor targeting the disease-driven active conformation of mutant EGFRs, allowing super-potency against diverse EGFR oncogenic drivers and resistance mutations while sparing wildtype EGFR. Aiming to characterize how this novel, super-potent OMNI-EGFR inhibitor could address the resistance liabilities of contemporary EGFR TKIs, BH-30643 was studied alongside 10 contemporary EGFR TKIs, approved or in clinical studies with a panel of primary cancer or engineered Ba/F3 cell lines expressing classical EGFR mutation (ex19del or L858R) or compound resistance mutations (T790M, C797S, or both). EGFR C797S conferred resistance to 6 covalent EGFR TKIs, T790M rendered resistance to 4 EGFR TKIs with a structure motif in EGFR back pocket, while the triple compound mutations with C797S and T790M were resistant to all 10 contemporary EGFR TKIs, leaving BH-30643 as the only TKI capable of overcoming both C797S and T790M resistance mutations while maintaining super potency against classical EGFR mutations. Furthermore, BH-30643 and osimertinib were investigated in a long-term colony formation assay in cancer cells with EGFR classical mutations. BH-30643 demonstrated markedly prolonged suppression of cell proliferation compared to osimertinib at the same clinically relevant concentration not only under standard growth conditions, but also in the presence of EGF, which mimicked accelerated resistance. These data support the potential of BH-30643, as a super-potent OMNI-EGFR TKI for longer duration of treatment than osimertinib. Upregulation of growth factors are well recognized as a common resistance mechanism for receptor TKIs. Targeting the active EGFR kinase conformation is hypothesized to reduce vulnerability to growth factor-mediated EGFR TKI resistance (eg, EGF). In the presence of EGFR ligands, BH-30643 maintained cell potency in all cell lines, while potency of osimertinib steeply fell, particularly in cells with EGFR L858R mutation. The first-in-human trial of BH-30643 (SOLARA) is now enrolling globally, with a focus on advanced EGFR -mutant NSCLC either with TKI resistance or prior to targeted therapy exposure (NCT06706076).