HotSpot Therapeutics Presents Preclinical Data for Potential First-in-Class MALT1 Scaffolding Inhibitor at 65th ASH Annual Meeting

Oral presentation describes distinct preclinical profile for potent, selective MALT1 scaffolding inhibitor that is highly differentiated from MALT1 protease inhibitors

BOSTON, Mass., Dec. 11, 2023 – HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as “natural hotspots,” today announced the presentation of preclinical data from the Company’s highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program in an oral presentation at the 2023 American Society of Hematology (ASH) Annual Meeting.

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 Allostery^TM platform, HotSpot has developed potential first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway, while sparing MALT1’s protease function.

“MALT1’s therapeutic potential rests in the role of its scaffolding function to regulate the NFkB pathway, which is implicated in a broad range of hematological and solid tumors,” said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. “Using our Smart Allostery^TM platform, HotSpot has delivered a potential first-in-class allosteric inhibitor, HST-1021, that is designed to potently and selectively inhibit MALT1’s scaffolding function. HST-1021’s pharmacological attributes suggest therapeutic potential, as these preclinical data demonstrated in vivo tumor growth inhibition without any observed negative impact on other immune functions. We look forward to providing additional updates as we advance our program, as we plan to file an Investigational New Drug (IND) application for HST-1021 in 2024.”

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 inhibitor development candidate:

• Using the Smart Allostery^TM platform, HotSpot elucidated and drugged a natural hotspot on MALT1 that potently and selectively inhibited MALT1’s scaffolding function, while sparing MALT1’s protease function.
• In several B-cell lymphoma xenograft models, HST-1021 demonstrated robust, dose-dependent tumor growth inhibition (TGI), including in both MALT1 protease-inhibitor sensitive ABC-DLBCL and MALT1 protease-resistant NFkB-driven DLBCL models.
• In contrast to MALT1 protease inhibitors, HotSpot’s scaffolding inhibitor did not deplete Treg cells or suppress T-cell activation in vivo, which HotSpot believes supports the potential for clinical mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and would allow for broad combination use.

About HotSpot Therapeutics, Inc.

HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called “natural hotspots.” These pockets are decisive in controlling a protein’s cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company’s proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit www.hotspotthera.com.

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Natalie Wildenradt

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