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Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes.

McGregor LM, Jenkins ML, Kerwin C, Burke JE, Shokat KM
Biochemistry 56 3178-3183 (2017)
Cited: 32 times
EuropePMC logo PMID: 28621541

Abstract

There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation.

Articles - 5v6v mentioned but not cited (5)

  1. Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes. McGregor LM, Jenkins ML, Kerwin C, Burke JE, Shokat KM. Biochemistry 56 3178-3183 (2017)
  2. WIDOCK: a reactive docking protocol for virtual screening of covalent inhibitors. Scarpino A, Petri L, Knez D, Imre T, Ábrányi-Balogh P, Ferenczy GG, Gobec S, Keserű GM. J Comput Aided Mol Des 35 223-244 (2021)
  3. Organization of Farnesylated, Carboxymethylated KRAS4B on Membranes. Barklis E, Stephen AG, Staubus AO, Barklis RL, Alfadhli A. J Mol Biol 431 3706-3717 (2019)
  4. DUckCov: a Dynamic Undocking-Based Virtual Screening Protocol for Covalent Binders. Rachman M, Scarpino A, Bajusz D, Pálfy G, Vida I, Perczel A, Barril X, Keserű GM. ChemMedChem 14 1011-1021 (2019)
  5. In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders. Leini R, Pantsar T. J Chem Inf Model 63 1490-1505 (2023)


Reviews citing this publication (8)

  1. The current understanding of KRAS protein structure and dynamics. Pantsar T. Comput Struct Biotechnol J 18 189-198 (2020)
  2. Structure-based design of targeted covalent inhibitors. Lonsdale R, Ward RA. Chem Soc Rev 47 3816-3830 (2018)
  3. Behind the Wheel of Epithelial Plasticity in KRAS-Driven Cancers. Arner EN, Du W, Brekken RA. Front Oncol 9 1049 (2019)
  4. Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies. Turpin A, Neuzillet C, Colle E, Dusetti N, Nicolle R, Cros J, de Mestier L, Bachet JB, Hammel P. Ther Adv Med Oncol 14 17588359221118019 (2022)
  5. Structure-based inhibitor design of mutant RAS proteins-a paradigm shift. Nyíri K, Koppány G, Vértessy BG. Cancer Metastasis Rev 39 1091-1105 (2020)
  6. Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery. McAulay K, Bilsland A, Bon M. Pharmaceuticals (Basel) 15 1366 (2022)
  7. Advanced approaches of developing targeted covalent drugs. Gai C, Harnor SJ, Zhang S, Cano C, Zhuang C, Zhao Q. RSC Med Chem 13 1460-1475 (2022)
  8. Dynamic structural biology at the protein membrane interface. Burke JE. J Biol Chem 294 3872-3880 (2019)

Articles citing this publication (19)



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