HotSpot Therapeutics Unveils Preclinical Data for Novel MALT1 Inhibitor at AACR Lymphoma Meeting

HotSpot Therapeutics, Inc., a biotechnology company based in Boston, has announced promising preclinical data for its innovative MALT1 scaffolding inhibitor, HST-1021, at the 4th American Association for Cancer Research (AACR) International Meeting focusing on advances in malignant lymphoma. MALT1, a key component of the CARD11-BCL10-MALT1 (CBM) protein complex, plays a critical role in activating the NF-kB signaling pathway in cells, particularly B and T cells. This pathway is implicated in various hematological cancers, including Non-Hodgkin's lymphoma, as well as some solid tumors.

The company's Smart Allostery™ platform has enabled the development of HST-1021, a potentially first-in-class small molecule designed to selectively inhibit the scaffolding function of MALT1. This inhibition is crucial as it directly affects the NF-kB pathway, a known oncogenic driver in numerous cancers, without disrupting MALT1's protease function. This selectivity is intended to minimize the risk of autoimmune diseases linked to chronic inhibition of MALT1 protease activity.

Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot, highlighted the significance of targeting the NF-kB pathway through MALT1's scaffolding function. The preclinical data presented revealed that HST-1021 effectively inhibits NF-kB and AP1 activities in vitro, which are key markers of MALT1's scaffolding activity. Unlike MALT1 protease inhibitors, HST-1021 did not impact MALT1 protease activity or T-cell function, nor did it deplete regulatory T cells (Treg) in vivo. This indicates a reduced risk of autoimmune complications and suggests that HST-1021 could be used in combination therapies.

The preclinical studies further demonstrated that HST-1021 exhibited broader and more significant anti-tumor activity compared to MALT1 protease inhibitors. This positions HST-1021 as a promising candidate for treating various cancers driven by the NF-kB pathway.

HotSpot Therapeutics is at the forefront of developing allosteric drugs that target regulatory sites on proteins identified as "natural hotspots." These hotspots are critical for controlling protein functions within cells, presenting new opportunities for drug discovery. The company's proprietary Smart Allostery™ platform leverages computational methods and AI-driven data analysis to identify these hotspots. This platform integrates tailored pharmacology toolkits and custom chemistry to expedite the discovery of novel, potent, and selective small molecules.

The company is building a diverse pipeline of allosteric therapies aimed at treating cancer and autoimmune diseases by targeting these natural hotspots. HotSpot Therapeutics' approach represents a significant advancement in the systematic design of small molecules with unique pharmacological properties, poised to address unmet medical needs in oncology and beyond.