Targeting EZH2 and EGFR Therapeutic Vulnerabilities of TNBC with a Single Chemical Entity Confers Preclinical Treatment Advantage.

Globally, Triple-Negative Breast Cancer (TNBC) has huge unmet medical need as it has limited targeted therapeutic options. However, it has well-known therapeutic vulnerabilities for selective inhibition of pathways like EGFR, m-TOR, PARP, EZH2, PD1-PDL1 etc. Analysis of publicly available databases clearly suggest that the concomitant EZH2 and EGFR overexpression results in poor survival of TNBC patients compared to their individual overexpression, underscoring the strong rationale for dual-targeted therapeutic intervention. Herein, potent, tumor cell selective chemical probes were designed and synthesized that simultaneously binds to both EZH2 and EGFR and inhibit their pro-tumorigenic functions in TNBC. SAR driven optimized lead molecule S-023-0996 (41a) proficiently binds and inhibits dual targets dampening tumor cell proliferation, migration and invasion in vitro with superior efficacy and safety than individual drug combinations (EZH2 inhibitor, Tazemetostat and EGFR inhibitor, Gefitinib). Mass spectrometry-based proteomic profiling revealed translation inhibition is a key differentiating factor for achieving robust anti-tumor effects of S-023-0996. S-023-0996 has favourable pharmacokinetic properties and inhibits tumor growth and metastasis in vivo more efficiently than comparator drug combinations in preclinical TNBC models. Our results represent the discovery of first-in-class dual EZH2-EGFR inhibitor and establish the possibility of targeting two vulnerabilities of TNBC together with a single chemical entity.