Pipeline - HotSpot Therapeutics
Pipeline of Novel Targets
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.
Program Overview
| Program | Lead Candidate | Indication | Stage |
|---|---|---|---|
| Inflammation | HST-2011 | SLE, Sjögren’s, RA, SSc, myositis | IND-enabling |
IRF5
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.
Program Overview
| Program | Lead Candidate | Indication | Stage |
|---|---|---|---|
| Serious Autoimmune Disorders | Undisclosed | Genetically validated target for serious autoimmune disorders | Discovery |
CBL-B
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.
Program Overview
| Program | Lead Candidate | Indication | Stage |
|---|---|---|---|
| CBL-B | HST-1011 | Solid tumors | Phase 1 |
CBM
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.
Focus on Patients and Value Creation
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.
Presentations
June 6, 2026
Preclinical and Translational Assessment of Small Molecule IRF5 Inhibitors in Lupus-Relevant Systems
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March 6, 2026
Preclinical Evaluation of IRF5 Small Molecule Inhibitors with Potent Activity in Lupus-Relevant Systems
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July 4, 2025
MSS/KRASG12XCRC Depends on CBM Signalosome for Survival - A Discovery that May Transform KRASG12XCRC Therapy
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July 4, 2025
Synthetic Lethality of CBM Signalosome Inhibition for KRASG12X Colorectal Cancer
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June 26, 2025
Targeting IRF5: Discovery and Preclinical Development of Selective Small Molecule Inhibitors
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November 9, 2024
Peripheral Blood and Tumor Gene Expression as Biomarkers and Potential Predictors of Clinical Outcome with HST-1011, an Oral CBL-B Inhibitor
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October 23, 2024
Targeting the CBM Signalosome with a MALT1 Signalosome Glue for Treatment of NFκB Driven Solid Tumors
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September 13, 2024
First-in-Human (FIH) Phase 1 Data of HST-1011, an Oral CBL-B Inhibitor, in Patients with Advanced Solid Tumors
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June 20, 2024
Targeting the CBM Signalosome with a MALT1 Scaffolding Inhibitor for Treatment of Non-Hodgkin Lymphomas
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December 9, 2023
Discovery of the First MALT1 Allosteric Scaffolding Inhibitor
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November 3, 2023
Exploring Proximal Biomarkers of CBL-B Inhibition in Human Peripheral Blood Mononuclear Cells
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April 19, 2023
Inhibition of the E3 Ligase CBL-B Enhances the Effector Function and Proliferation of Natural Killer (NK) Cells
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April 18, 2023
Phase 1/2 Study of HST-1011, an Oral CBL-B Inhibitor, Alone and in Combination with Anti-PD-1 in Patients with Advanced Solid Tumors
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November 11, 2022
CBL-B Inhibition Showed Differentiated Effects in a Mixed Lymphocyte Reaction Versus Other Immuno-oncology Targeted Approaches
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November 11, 2022
An Allosteric, Orally Administered CBL-B Inhibitor Remodels the Tumor Microenvironment and Enhances Immune-mediated Tumor Growth Inhibition
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April 10, 2022
A Novel Allosteric CBL-B Inhibitor with Differentiated Immune Enhancing Activity in Preclinical Models
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November 10, 2021
Identification of A Novel Allosteric Oral CBL-B Inhibitor that Augmented T Cell Response and Enhanced NK Cell Killing in vitro and in vivo
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Our Team
HotSpot Therapeutics is led by a team of seasoned drug hunters with substantial industry and R&D expertise.