On October 23, 2024 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," reported it will present preclinical data from the Company’s mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (Press release, HotSpot Therapeutics, OCT 23, 2024, View Source [SID1234647352]).
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MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.
"Our proprietary Smart Allostery platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1’s scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021’s potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway."
The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 CBM signalosome glue development candidate:
In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity.
In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021’s potential for the treatment of NF-kB-driven solid tumors.