Accuronix Therapeutics is a leader in discovering and developing a new class of drugs that work by selectively targeting the σ-2 (sigma-2) receptor on cancer cells to deliver cytotoxic payloads. The Accuronix team has established an innovative platform and a lead drug candidate based on advances in characterizing the molecular-targeted drug conjugate (MTDC) approach to cancer therapy. The σ-2 receptors are highly expressed on the surface of rapidly proliferating cancer cells. They internalize upon ligand binding, allowing the delivery of therapeutic agents to intracellular targets. The result is a chemotherapeutic with increased effectiveness and reduction in toxicity risk.
In January 2016, Accuronix licensed our σ-2-based technology from Washington University in St. Louis and assembled a team of experienced biotech scientists and executives, the technology originators, and key executional partners. Accuronix’s σ-2 platform enables the discovery of selective molecularly targeted drug conjugates for a variety of therapeutic cargoes to treat a range of cancers. We are working to advance the development of the lead candidate, ACXT-3102 for pancreatic adenocarcinoma and other rare tumor types; and to progress next-generation MTDCs into development for other oncology indications.
σ-2 Molecularly Targeted Drug Conjugates Overview
σ-2 molecularly targeted drug conjugates Science
Accuronix is pioneering pharmaceutical development of selective delivery of small molecule cargos into cancer cells based on the σ-2 ligand/receptor system. σ-2 receptors are overexpressed in most human cancers, including pancreatic, and select σ-2 ligands can deliver drug cargoes as chemical conjugates into cancer cells.
Our founders demonstrated that the σ-2 platform has been able to convert an underperforming chemotherapeutic into a potent anti-tumor therapy. σ-2 ligands have been conjugated with a number of therapeutic warheads.
σ-2 receptor probes have also been linked to radioisotopes and fluorescent markers to image solid tumors with PET/CT. These σ-2 ligands localize to pancreatic cancer tumors in animal models and to breast and head & neck cancer in patients. In addition to their high selectivity for the σ-2 receptor in cancer cells, a key feature of σ-2 ligands is rapid cellular uptake and internalization.
The MDTC ACXT-3102 links a σ-2 ligand to des-methyl-erastin.
σ-2 receptors are highly expressed on the surface of rapidly proliferating cancer cells, but not healthy ones. The ligand bound receptors rapidly internalize. σ-2 receptors also have subcellular localization in mitochondria, endoplasmic reticulum and plasma membranes, providing potential additional targeted sites of drug action.
Erastin induces tumor cell death by inhibiting cystine uptake via the cystine/glutamate antiporter (system xc-) on plasma membranes. Cell death occurs via ferroptosis, a non-apoptotic, iron-dependent, oxidative cell death.
In its native form, erastin has poor cellular uptake, but when des-methyl-erastin is conjugated to σ-2 ligands, cell death has been demonstrated in multiple tumor lines. In addition, the MTDC ACXT-3102 has been shown to cause tumor stabilization or regression as well as significantly increased survival in several murine pancreatic tumor models.