Context’s transformative approach to modulating Sigma1 protein function opens up a vast new domain for discovering new medicines.
Sigma1 is an intracellular protein that engages in client protein complex formation to regulate the quality control, transport, and activity of client proteins. By therapeutically modulating Sigma1 stabilization of client proteins, client protein transport is altered, leading to positive or negative regulation of client protein signaling pathways. Many of these client proteins are validated disease targets but are generally considered undruggable through small molecule approaches. Indirect modulation of client protein stability and transport through Sigma1 expands the universe of opportunities for new drug discovery and new treatments for patients.
Sigma1 modulation offers vast potential for treating diseases that cannot be addressed by any other means.
Context is focused on diseases where there is clear genetic validation for Sigma1 as a drug target and where biomarker stratification of patients is possible:
- Oncology. Sigma1 stabilizes oncoproteins that drive proliferation of select solid and liquid tumors.
- Fibrosis. Treating fibrosis requires multimodal or combination therapies that down-regulate proliferative and immune signals that drive disease progression. Sigma1 client proteins are key regulators of these disease pathways and can be indirectly targeted through Sigma1 inhibition.
- Neurology. Sigma1 mutations are associated with early onset neurodegenerative diseases, including ALS and Alzheimer's.
Lead Program - Advanced Prostate Cancer
Androgen receptor (AR) signaling is the primary driver of prostate cancer disease progression, resulting in about 30,000 deaths per year in the US. Current treatments do not address, and often enhance, resistance mechanisms that drive AR transport and subsequent activation of AR signaling programs that promote cancer cell survival.
Context scientists were the first to establish that enhanced Sigma1 expression and Sigma1-mediated transport of androgen receptor is associated with malignancy. Context has developed and characterized a series of drug-like small molecule Sigma1 modulators that disrupt Sigma1-mediated stabilization of AR as well as mutants and variants of AR that are resistant to all currently available therapeutic agents, allowing rapid translation of preclinical studies to Phase I trials.
New Sigma1 Indications
Our strategy includes collaborating with academic and biopharmaceutical partners. We have a flexible resource sharing program - our Sigma1 Toolkit - to enable the expedited transfer of our chemical library, reagents, and biomarker tools for groups interested in our core research areas and outside.
Context has developed proprietary reagents and tools to evaluate target engagement, pharmacodynamic response, and patient enrichment across disease states. Our goal is not only to develop new and effective drugs, but to identify those patients who are most likely to benefit.
Tools to monitor client protein activation and signaling pathways.
Therapeutically-induced modulation of Sigma1 structure and function.
Transcriptomic-based tools for predicting response to Sigma1 therapeutics.