At HotSpot, we are advancing a pipeline of therapeutic candidates for the treatment of cancer and 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.
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. Robust preclinical data demonstrate a central role of CBL-B inhibition to immune cell activation and immune-mediated tumor growth inhibition in vivo, supporting the therapeutic potential of this mechanism.
Our lead development candidate, HST-1011, has the potential to be a first-in-class selective, orally bioavailable, small molecule targeting CBL-B for the treatment of patients with solid tumors. HST-1011 was designed to have picomolar binding affinity, low nanomolar potency, slow rate of dissociation from the target to enable potency and sustained pharmacology, and greater selectivity for CBL-B relative to C-CBL, another E3 ligase originating from the same protein superfamily. The planned Phase 1 evaluation of HST-1011 will focus on patients who are relapsed or refractory to anti-PD(L)1-based therapies as an opportunity to demonstrate both the biological effects of CBL-B inhibition in humans and to support the opportunity to address significant clinical need.
MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NFkB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin’s lymphoma, as well as other lymphomas and selected solid tumors. Leveraging our proprietary Smart AllosteryTM platform, HotSpot has developed first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway. HotSpot’s scaffolding inhibitor has a differentiated preclinical profile, including the potential for an improved efficacy and safety profile versus traditional MALT1 inhibitors that target protease function. HotSpot plans to file an IND for HST-1021, its Development Candidate, in 2024.
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 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 small molecule IRF5 inhibitors that bind to a previously unknown allosteric pocket on the protein that is critical for its endogenous regulation.
In collaboration with AbbVie, we are developing our IRF5 inhibitor program for the treatment of multiple autoimmune diseases including SLE, Sjögren’s, RA, 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.
Our pipeline is further enabled by biomarker-driven, patient-targeted approaches in oncology and autoimmune diseases. To support these efforts, in 2021, we entered into a collaboration with Caris Life Sciences.
We believe Caris’ comprehensive suite of tissue and liquid profiling, real-world data, and broader capabilities will enable robust interrogation of large datasets, yielding data-informed insights to inform and speed clinical development and deliver new treatment options to patients.