HotSpot Therapeutics, Inc., a biotech company pioneering the discovery and development of oral, small molecule allosteric therapies targeting Smart Allostery platform-identified regulatory sites on proteins referred to as “natural hotspots,” has announced the presentation of preclinical data from the company’s CARD11-BCL10-MALT1 (CBM) signalosome programme at the European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress 2025.
The CBM 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 tumour 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 tumour inhibition and regression in multiple KRAS-driven tumour models.
“While KRAS activation is a prominent genetic feature of CRC, KRAS inhibitors do not yield deep or durable responses for the vast majority of CRC patients. For the first time, we have shown that KRASG12X CRC depends on the CBM signalosome for survival, supporting the significant potential of a CBM signalosome inhibitor to transform the treatment landscape of KRASG12C CRC, as well as additional KRAS-associated solid tumours,” said Geraldine Harriman, chief scientific officer of HotSpot Therapeutics.
“Leveraging our Smart Allostery platform, we have developed potent inhibitors of the CBM signalosome complex, with robust in vitro and in vivo data demonstrating apoptosis and tumor growth inhibition and regression in KRASG12C CRC, providing support for the profound clinical potential of a CBM signalosome inhibitor.”
The poster presentations describe the following data:
HotSpot’s CBM signalosome inhibitors demonstrated selectively induced potent apoptosis in KRASG12 CRC cell lines, outperforming KRAS, BCL2 and Bcl-xL inhibitors.
In combination with a KRAS inhibitor, HotSpot’s CBM signalosome inhibitor achieved complete suppression of downstream signaling in KRASG12X cell lines.
HotSpot’s CBM signalosome inhibitor demonstrated dose-dependent tumour inhibition or regression both alone and in combination with a KRAS inhibitor in multiple in vivo models.
Jim Cornall is editor of Deeptech Digest and publisher at Ayr Coastal Media. He is an award-winning writer, editor, photographer, broadcaster, designer and author. Contact Jim here.
