Targeting mutant estrogen receptor driven breast cancers

Etirarx, Llc, Dallas TX

Investigators

Abstract

Project Summary/Abstract A majority of Breast cancers (BC) express estrogen receptor alpha (ER?). While endocrine therapies targeting either estrogen production or ER? are effective, acquired resistance is common. Sequencing of metastatic endocrine therapy-resistant (ETR) tumors has shwown that ER? 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 ER? mutations in ETR-BC represent a significant unmet clinical need. We leveraged the recent structural characterization of the mutant ER? 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 ER? LBD. Our preliminary studies showed that ERX-315 has potent anti-proliferative activity against mutant ER?-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 ER? 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 ER?, 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 ER?, including selective ER? 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 ER?, 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.