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Small-molecule degraders for oncogenic KRAS^G12C and pan-KRAS mutations

Jianxiong Deng^1,2,3, Shujun Shen^1,2,3, Lei Huang^1,2,3

¹State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.

Nature Communications

|March 27, 2026

Abstract:

KRAS, a frequently mutated oncogene, has been challenging to target therapeutically. Although covalent inhibitors like sotorasib against KRAS^G12C have been developed, their efficacy is often limited by acquired resistance. Targeted protein degradation offers a potential solution but has largely relied on large PROTAC molecules. Here, we report DJX-A-KM, a small-molecule degrader of KRAS^G12C, designed by incorporating an acrylamide warhead into the MRTX849 scaffold. It induces potent and sustained degradation of KRAS^G12C in cells and in vivo. Mechanistic investigation reveal that degradation is mediated by the ubiquitin-proteasome system, facilitated by covalent engagement with a E3 ligase, FBXO28, at cysteine 98. Antiproliferation assays demonstrate its potent inhibitory effects across multiple KRAS^G12C-mutant cancer models. This strategy also enables the development of pan-KRAS degraders against a broader spectrum of KRAS mutations. Our work presents a small-molecule degrader recruiting FBXO28 and provides a blueprint for exploring E3 ligases in protein degradation.

Insights

A novel small molecule, DJX-A-KM, effectively degrades KRAS G12C, overcoming resistance to current therapies. This targeted protein degrader shows promise for treating KRAS-mutant cancers and developing broader KRAS inhibitors.

Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

KRAS is a key oncogene frequently mutated in various cancers.
Targeting KRAS G12C mutations with covalent inhibitors like sotorasib shows limited efficacy due to acquired resistance.
Targeted protein degradation offers an alternative therapeutic strategy, but often requires large molecules.

Purpose of the Study:

To develop a small-molecule degrader for KRAS G12C.
To investigate the mechanism of action and efficacy of the novel degrader.
To explore the potential for developing pan-KRAS degraders.

Main Methods:

Design of DJX-A-KM by incorporating an acrylamide warhead into the MRTX849 scaffold.
Assessment of KRAS G12C degradation in vitro and in vivo.
Mechanistic studies involving ubiquitin-proteasome system and E3 ligase interaction.
Antiproliferation assays in KRAS G12C-mutant cancer models.

Main Results:

DJX-A-KM induces potent and sustained degradation of KRAS G12C.
Degradation is mediated by the ubiquitin-proteasome system via covalent engagement with FBXO28.
DJX-A-KM exhibits potent antiproliferative effects in KRAS G12C-mutant cancer models.
The strategy shows potential for developing pan-KRAS degraders.

Conclusions:

DJX-A-KM is a novel small-molecule KRAS G12C degrader with therapeutic potential.
The study highlights FBXO28 as an E3 ligase for targeted protein degradation.
This approach provides a blueprint for developing new degraders against KRAS mutations and other targets.

Read full analysis

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