Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC

Area of Science:

• Oncology
• Chemical Biology
• Molecular Biology

Background:

• MYC is a key oncogenic transcription factor driving cancer.
• Directly targeting MYC is challenging due to its disordered structure, making it
• undruggable.
• Targeting transient pockets in unstructured protein regions with small molecules is an ongoing challenge.

Purpose of the Study:

• To develop a novel covalent ligand library to target and degrade MYC.
• To identify and characterize small molecules that can destabilize and degrade MYC.
• To explore the druggability of intrinsically disordered regions in transcription factors.

Main Methods:

• Development of a stereochemically paired spirocyclic oxindole aziridine covalent library.
• Screening the library for MYC degradation activity.
• Characterization of the hit compound's mechanism of action, including MYC/MAX engagement and proteasome-dependent degradation.
• Site-directed mutagenesis of MYC residues C203 and D205.

Main Results:

• Identification of a covalent ligand, KL2-236, with a sulfinyl aziridine warhead that engages MYC.
• KL2-236 destabilizes MYC, inhibits its transcriptional activity, and induces proteasome-dependent degradation by targeting C203 and D205 residues.
• Stereoisomers of KL2-236 showed differential activity, with specific isomers being more potent.
• Optimization led to KL4-219A, a more potent, selective, and durable MYC degrader.

Conclusions:

• Intrinsically disordered regions of MYC can be targeted by isomerically unique chiral small molecules.
• This approach leads to MYC destabilization and degradation, offering a novel therapeutic strategy.
• The findings reveal a new ligandable site within MYC and validate targeting disordered regions in transcription factors.