HotSpot Therapeutics Inc, a US-based biotechnology company involved in the discovery and development of oral, small molecule allosteric therapies targeting Smart Allostery platform-identified regulatory sites on proteins referred to as 'natural hotspots', announced on Friday 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.

According to HotSpot, 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 its 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.

The poster presentations describe how: 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 signalling in KRASG12X cell lines; and 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.