Compounds and methods for FBXW7-R465C-mediated protein degradation

NU 2024-224

INVENTORS

• Xiaoyu Zhang*
• Ananya Basu

SHORT DESCRIPTION

This invention describes novel heterobifunctional compounds that exploit a somatic mutant of the FBXW7 E3 ligase for targeted protein degradation.

BACKGROUND

Targeted protein degradation (TPD) is a powerful therapeutic strategy that harnesses the cell's natural machinery to eliminate specific proteins. A major challenge in this field is the limited number of E3 ubiquitin ligases currently employed; despite over 600 E3 ligases in the human genome, most TPD applications predominantly utilize only two, CRBN and VHL. This narrow scope restricts the range of proteins that can be effectively targeted and limits the broader therapeutic applicability of TPD. Moreover, existing approaches often lack the ability to selectively degrade proteins exclusively in diseased cells, which can lead to off-target effects in healthy tissues. There is a critical need for more precise and selective degradation strategies that can differentiate between healthy and diseased cells, ideally by leveraging unique, disease-specific molecular features to enhance therapeutic efficacy and reduce adverse effects.

ABSTRACT

Northwestern researchers discovered a TPD strategy that exploits the somatic R465C mutation in the E3 ubiquitin ligase FBXW7, a recurrent hotspot mutation most commonly found in colorectal and endometrial tumors, to achieve selective protein degradation. The acquired R465C mutation in cancer cells is covalently engaged by novel electrophilic heterobifunctional compounds. These compounds simultaneously bind a target protein of interest, forming a ternary complex between mutant FBXW7-R465C, the compound, and the target protein. This induced proximity facilitates the ubiquitination of the target protein by the hijacked FBXW7-R465C, and subsequent degradation by the proteasome. This mechanism enables the selective degradation of target proteins exclusively in cells harboring the FBXW7-R465C mutation, thereby expanding the repertoire of E3 ligases available for TPD and offering a disease-specific therapeutic approach.

APPLICATIONS

• Precision cancer therapeutics – enables the development of selective cancer drugs that degrade disease-driving proteins specifically in cells harboring the FBXW7 R465C mutation
• TPD platform development – provides a novel methodology for expanding the repertoire of available E3 ligases for cancer therapeutics
• Research tool – provides novel compounds for drug discovery and mechanistic studies on protein degradation pathways

ADVANTAGES

• Selectivity for mutant cells - improved therapeutic index and reduced potential for off-target effects
• Expansion of E3 ligases available for TPD beyond CRBN and VHL
• Potential to overcome resistance mechanisms observed with traditional PROTAC therapies utilizing CRBN and VHL
• Applicability to several cancer types - the recurrent FBXW7 R465C mutation in colorectal, endometrial, and T-cell leukemias enables broad applicability in mutation-bearing tumors.

PUBLICATIONS

Basu et al. Harnessing the FBXW7 Somatic Mutant R465C for Targeted Protein Degradation. Journal of the American Chemical Society, 2025.

IP STATUS

A US non-provisional patent has been filed.