Malolactone strikes: K-Ras-G12D's Achilles' heel

Christos Adamopoulos; Kostas A Papavassiliou; Athanasios G Papavassiliou

doi:10.1016/j.tips.2024.04.001

Malolactone strikes: K-Ras-G12D's Achilles' heel

Trends Pharmacol Sci. 2024 Apr 22:S0165-6147(24)00066-X. doi: 10.1016/j.tips.2024.04.001. Online ahead of print.

Authors

Christos Adamopoulos¹, Kostas A Papavassiliou², Athanasios G Papavassiliou³

Affiliations

¹ Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² First University Department of Respiratory Medicine, 'Sotiria' Hospital, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece.
³ Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece. Electronic address: papavas@med.uoa.gr.

PMID: 38653668
DOI: 10.1016/j.tips.2024.04.001

Abstract

In a recent study in Nature Chemical Biology, Zheng et al. exploiting strain release by malolactone-based electrophiles and designed a first-in-class covalent inhibitor that targets the elusive aspartate of the Kirsten rat sarcoma viral oncogene homolog (K-Ras)-G12D variant, which is highly prevalent in pancreatic cancer. The compound drastically inhibited oncogenic signaling and tumor growth in preclinical K-Ras-G12D-mutant pancreatic cancer models, expanding treatment potential beyond K-Ras-G12C-targeted therapies.

Keywords: K-Ras-G12D; alkylation; covalent inhibitor; malolactone; strain release.