By targeting natural hotspots with novel allosteric chemistry, important disease biology can be unlocked for the first time.
At HotSpot, we are advancing a pipeline of therapeutic candidates for the treatment of autoimmune diseases where there remains a significant unmet need. Our Smart Allostery™ platform has allowed us to deliver differentiated small molecule allosteric inhibitors that address key challenges for targets with deep genetic and/or biologic validation.
Interferon regulatory factor 5, or IRF5, is a transcription factor involved in a diverse range of biological activities in which it functions as a master regulator of innate immunity. Genome-wide association studies have established compelling evidence as to the involvement of IRF5 in multiple inflammatory and immune system disorders, including systemic lupus erythematosus, or SLE, making it a development target of significant interest. Historical efforts to modulate IRF5 using traditional small molecule approaches have been unsuccessful because IRF5 lacks a traditional active site. Leveraging our proprietary Smart Allostery™ platform, we believe we have discovered the first and only potent and selective small molecule IRF5 inhibitors that bind to a previously unknown allosteric pocket on the protein that is critical for its endogenous regulation.
We are developing our IRF5 inhibitor program for the treatment of multiple autoimmune diseases including SLE/cutaneous lupus erythematosus, or CLE, Sjögren’s disease, rheumatoid arthritis, or RA, systemic sclerosis, or SSc, and myositis.
Our undisclosed immunology program is designed to inhibit a genetically validated target with strong disease associations for a range of serious autoimmune diseases. At HotSpot, we are leveraging our Smart Allostery™ platform to develop differentiated inhibitors for this target.
Casitas B-lineage Lymphoma-B, or CBL-B, is an E3 ubiquitin protein ligase critically involved in immune cell response. CBL-B is a master regulator of effector cell (T cell and natural killer cell) immunity, and its elimination or inactivation removes its endogenous negative regulatory functions to substantially enhance anti-tumor immunity. In a Phase 1 study, HotSpot’s CBL-B inhibitor candidate HST-1011 showed an encouraging early clinical profile demonstrating important linkages between exposure, target engagement, pharmacodynamics and initial signs of clinical activity, along with a generally manageable safety profile, in heavily pre-treated patients with advanced solid tumors.
The CBM, or CARD11-BCL10-MALT1 signalosome is a molecular hub that serves as a key regulator of multiple oncogenic pathways, including NFkB, JNK, mTORC1 and MYC. As such, the CBM signalosome serves as a critical regulator of tumor development and survival, particularly in KRAS-driven colorectal cancer (CRC), as well as other KRAS-driven cancers, including pancreatic and lung cancer. Leveraging the Company’s proprietary Smart Allostery™ platform, HotSpot has discovered small molecule CBM signalosome inhibitors that bind and inactivate the complex, with preclinical data demonstrating dose-dependent tumor inhibition and regression in multiple KRAS-driven tumor models.
At HotSpot, we are building a deep pipeline of therapeutic candidates focused on targets with strong genetic, pathway and mechanistic validation, including those where we can obtain important learnings via biomarker read-outs in preclinical and early clinical development. HotSpot’s pipeline is focused on autoimmune indications associated with unmet medical need that have the potential to be addressed with an oral, small molecule therapy.
