Etirarx, Inc.

Targeting Mutant Estrogen Receptor Driven Breast Cancers - Project Summary/abstract a Majority of Breast Cancers (BC) Express Estrogen Receptor Alpha (era). While Endocrine Therapies Targeting Either Estrogen Production or Era Are Effective, Acquired Resistance Is Common. Sequencing of Metastatic Endocrine Therapy-resistant (ETR) Tumors Has Shwown That Era Mutations Are Frequent (30-40%), Do Not Respond to Endocrine Therapies and Are the Molecular Drivers of Etr-bc. Thus, Drugs Designed to Specifically Target These Era Mutations in Etr-bc Represent a Significant Unmet Clinical Need. We Leveraged the Recent Structural Characterization of the Mutant Era Ligand Binding Domain (LBD) to Rationally Design Bis-benzamides to Fit the Binding Pocket. Following Iterative Rounds of Modeling, Synthesis, Testing and Optimization With >2000 Bis-benzamides, We Have Identified a Lead Compound, ERX-315, That Binds More Avidly to Era LBD. Our Preliminary Studies Showed That ERX-315 Has Potent Anti-proliferative Activity Against Mutant Era-driven Tumors, as Seen in Genetically Modified Cell Lines in Vitro, Patient Derived Explants (PDES) Ex Vivo and Patient Derived Xenografts (PDXS) in Vivo. Importantly, a Methylated Version of ERX-315, ERX-314 Binds the Mutant Era Poorly and Does Not Affect Proliferation of These Tumors. Ultrastructural and Molecular Studies Reveal That ERX-315, But Not ERX-314 (a Methylated Version of ERX-315, Does Not Bind Era, Serves as a Negative Control) Induces Significant Endoplasmic Reticulum Stress, Leading to a Shutdown of De Novo Protein Synthesis and Apoptotic Cell Death in BC. Importantly, ERX-315 Does Not Induce Endoplasmic Reticulum Stress or Cell Death in Normal Cells and Is Non-toxic in Animal Models. We Have Shown That This Capacity of Erx- 315 to Induce Endoplasmic Reticulum Stress Is Unique Among Drugs Targeting Era, Including Selective Era Modulators and Degraders, Such as GDC-0180, AXD-9496 and Fulvestrant. the Objective of This Direct Phase Ii Sbir Proposal Is to Enable Etirarx to Perform Ind-enabling Studies for Clinical Translation of ERX-315 in Etr-bcs. We Have Shown That ERX-315 Has Favorable Pharmacologic Parameters for Clinical Translation and Is Amenable to Good Manufacturing Practice Manufacturing. in Aim 1, We Will We Will Perform Dose-ranging Finding Studies in Two Species and Define Maximum Tolerated Dose and Toxicity at That Dose. in AIM2, We Will Synthesize Large-scale Batches of ERX-315 and Will Perform Single- and Multi-dose Pharmacokinetic Studies and Evaluate Tissue Biodistribution. We Will Define 30-DAY Toxicity in Rats and Dogs With a 2-WEEK Recovery, and Evaluate Functional Recovery, Cardiovascular and Respiratory Safety. in Aim 3, We Will Test the Efficacy of Clinical Grade ERX-315 in Biologically and Clinically Relevant Preclinical Models of Etr-bc, Including Patient Derived Xenografts and Patient Derived Explants. the Intellectual Property Around ERX-315 Is Protected by Multiple Patents Licensed to Etirarx. a Novel Small Molecule Targeting Mutant Era, and With an Unique Ability to Induce Endoplasmic Reticulum Stress and Apoptotic Cell Death. If Successful, Our Proposed Studies Will Enable Within 2 Years the First-in-class Studies With ERX-315 in Women With Etr-bc.