Abstract ND11: Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase

Abstract WRN helicase is a promising target for treating cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently, there are no approved drugs directly targeting human DNA or RNA helicases, in part due to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemical proteomic-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN. The clinical lead, VVD-214, covalently engages cysteine 727 of WRN in a nucleotide cooperative manner and inhibits ATP hydrolysis and helicase activity, resulting in widespread double-stranded DNA breaks, nuclear swelling, and cell death in MSI-high, but not microsatellite stable cells. VVD-214 provided robust tumor regression in multiple MSI-high colorectal cancer cell lines and patient derived xenograft models, including models derived from patients progressing on immune checkpoint therapies. VVD-214 was exceptionally well tolerated, and constitutes a promising oral drug candidate for patients with MSI-high cancers. Citation Format: Shota Kikuchi, Piergiorgio Pettazzoni, Kristen A. Baltgalvis, Kelsey N. Lamb, Kent T. Symons, Chu-Chiao Wu, Melissa A. Hoffman, Aaron N. Snead, Xiaodan Song, Thomas Glaza, Jason C. Green, Donald C. Rogness, Betty Lam, Maria E. Rodriguez-Aguirre, David R. Woody, Christie L. Eissler, Socorro Rodiles, Seth M. Negron, Steffen M. Bernard, Eileen Tran, Jonathan Pollock, Ali Tabatabaei, Victor Contreras, Heather N. Williams, Martha K. Pastuszka, John J. Sigler, Markus G. Rudolph, Moritz Classen, Doris Brugger, Christopher Claiborne, Jean-Marc Plancher, Isabel Cuartas, Joan Seoane, Laurence E. Burgess, Robert T. Abraham, David S. Weinstein, Gabriel M. Simon, Matthew P. Patricelli, Todd M. Kinsella. Chemoproteomic-enabled discovery of VVD-214, a synthetic lethal allosteric inhibitor of WRN helicase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND11.