Rosen, Hannah T., Li, Kelvin, Li, Ein L., Currier, Brynne, Brittain, Scott, Garcia, Francisco-1, Beard, Diana, Haenni-Holzinger, Sandra, Dovala, Dustin, McKenna, Jeffrey-1, Schirle, Markus, Maimone, Thomas J. and Nomura, Daniel K. (2025) Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC. Angewandte Chemie. International edition, 64. ISSN 1521-3773

Abstract

While MYC is a significant oncogenic transcription factor driver of cancer, directly targeting MYC has remained
challenging due to its intrinsic disorder and poorly defined structure, deeming it “undruggable.” Whether
transient pockets formed within intrinsically disordered and unstructured regions of proteins can be selectively
targeted with small molecules remains an outstanding challenge. Here, we developed a bespoke
stereochemically-paired spirocyclic oxindole aziridine covalent library and screened this library for degradation
of MYC. Through this screen, we identified a hit covalent ligand KL2-236, bearing a unique sulfinyl aziridine
warhead, that engaged MYC in vitro as pure MYC/MAX protein complex and in situ in cancer cells to
destabilize MYC, inhibit MYC transcriptional activity and degrade MYC in a proteasome-dependent manner
through targeting intrinsically disordered C203 and D205 residues. Notably, this reactivity was most
pronounced for specific stereoisomers of KL2-236 with a diastereomer KL4-019 that was largely inactive.
Mutagenesis of both C203 and D205 completely attenuated KL2-236-mediated MYC degradation. We have
also optimized our initial KL2-236 hit compound to generate a more durable MYC degrader KL4-219A in
cancer cells. Our results reveal a novel ligandable site within MYC and indicate that certain intrinsically
disordered regions within high-value protein targets, such as MYC, can be interrogated by isomerically unique
chiral small molecules, leading to destabilization and degradation.

Item Type:	Article
Date Deposited:	30 Dec 2025 00:45
Last Modified:	30 Dec 2025 00:45
URI:	https://oak.novartis.com/id/eprint/56653