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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)

  1. Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States. Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD, Renslo AR, Burke JE, Shokat KM. Cell Chem Biol 24 1455-1466.e14 (2017)
  2. KRAS(G12D) can be targeted by potent inhibitors via formation of salt bridge. Mao Z, Xiao H, Shen P, Yang Y, Xue J, Yang Y, Shang Y, Zhang L, Li X, Zhang Y, Du Y, Chen CC, Guo RT, Zhang Y. Cell Discov 8 5 (2022)
  3. 10 years into the resurgence of covalent drugs. De Vita E. Future Med Chem 13 193-210 (2021)
  4. Generation of KS-58 as the first K-Ras(G12D)-inhibitory peptide presenting anti-cancer activity in vivo. Sakamoto K, Masutani T, Hirokawa T. Sci Rep 10 21671 (2020)
  5. Covalent inhibition of NSD1 histone methyltransferase. Huang H, Howard CA, Zari S, Cho HJ, Shukla S, Li H, Ndoj J, González-Alonso P, Nikolaidis C, Abbott J, Rogawski DS, Potopnyk MA, Kempinska K, Miao H, Purohit T, Henderson A, Mapp A, Sulis ML, Ferrando A, Grembecka J, Cierpicki T. Nat Chem Biol 16 1403-1410 (2020)
  6. Novel K-Ras G12C Switch-II Covalent Binders Destabilize Ras and Accelerate Nucleotide Exchange. Nnadi CI, Jenkins ML, Gentile DR, Bateman LA, Zaidman D, Balius TE, Nomura DK, Burke JE, Shokat KM, London N. J Chem Inf Model 58 464-471 (2018)
  7. KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation. Lu J, Bera AK, Gondi S, Westover KD. Biochemistry 57 324-333 (2018)
  8. Quantitative Systems Pharmacology Analysis of KRAS G12C Covalent Inhibitors. Stites EC, Shaw AS. CPT Pharmacometrics Syst Pharmacol 7 342-351 (2018)
  9. Editorial Glimmers of hope for targeting oncogenic KRAS-G12D. Tang D, Kang R. Cancer Gene Ther 30 391-393 (2023)
  10. Stability and Cell Permeability of Sulfonyl Fluorides in the Design of Lys-Covalent Antagonists of Protein-Protein Interactions. Gambini L, Udompholkul P, Salem AF, Baggio C, Pellecchia M. ChemMedChem 15 2176-2184 (2020)
  11. The K-Ras(G12D)-inhibitory peptide KS-58 suppresses growth of murine CT26 colorectal cancer cell-derived tumors. Sakamoto K, Lin B, Nunomura K, Izawa T, Nakagawa S. Sci Rep 12 8121 (2022)
  12. An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4. Gonzalez-Valero A, Reeves AG, Page ACS, Moon PJ, Miller E, Coulonval K, Crossley SWM, Xie X, He D, Musacchio PZ, Christian AH, McKenna JM, Lewis RA, Fang E, Dovala D, Lu Y, McGregor LM, Schirle M, Tallarico JA, Roger PP, Toste FD, Chang CJ. J Am Chem Soc 144 22890-22901 (2022)
  13. An in situ combinatorial methodology to synthesize and screen chemical probes. van der Zouwen AJ, Lohse J, Wieske LHE, Hohmann KF, van der Vlag R, Witte MD. Chem Commun (Camb) 55 2050-2053 (2019)
  14. Strain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D. Zheng Q, Zhang Z, Guiley KZ, Shokat KM. Nat Chem Biol 20 1114-1122 (2024)
  15. Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors. Sakamoto K, Qi Y, Miyako E. Sci Rep 13 518 (2023)
  16. The war on hTG2: warhead optimization in small molecule human tissue transglutaminase inhibitors. Mader L, Watt SKI, Iyer HR, Nguyen L, Kaur H, Keillor JW. RSC Med Chem 14 277-298 (2023)
  17. On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors. Bonatto V, Batista PHJ, Cianni L, De Vita D, Silva DG, Cedron R, Tezuka DY, de Albuquerque S, Moraes CB, Franco CH, Lameira J, Leitão A, Montanari CA. RSC Med Chem 11 1275-1284 (2020)
  18. Contribution of Noncovalent Recognition and Reactivity to the Optimization of Covalent Inhibitors: A Case Study on KRasG12C. Péczka N, Ranđelović I, Orgován Z, Csorba N, Egyed A, Petri L, Ábrányi-Balogh P, Gadanecz M, Perczel A, Tóvári J, Schlosser G, Takács T, Mihalovits LM, Ferenczy GG, Buday L, Keserű GM. ACS Chem Biol 19 1743-1756 (2024)
  19. Crystallographic Studies of KRAS in Complex with Small Molecules and RAS-Binding Proteins. Chan AH, Simanshu DK. Methods Mol Biol 2797 47-65 (2024)


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