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Structural insights into drug development strategy targeting EGFR T790M/C797S.

Zhu SJ, Zhao P, Yang J, Ma R, Yan XE, Yang SY, Yang JW, Yun CH
Oncotarget 9 13652-13665 (2018)
Related entries: 5x27, 5x28, 5x2a, 5x2c, 5x2f, 5x2k

Cited: 16 times
EuropePMC logo PMID: 29568384

Abstract

Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.

Articles - 5x26 mentioned but not cited (1)

  1. Structural insights into drug development strategy targeting EGFR T790M/C797S. Zhu SJ, Zhao P, Yang J, Ma R, Yan XE, Yang SY, Yang JW, Yun CH. Oncotarget 9 13652-13665 (2018)


Reviews citing this publication (3)

  1. Toward structure-based drug design against the epidermal growth factor receptor (EGFR). Haddad Y, Remes M, Adam V, Heger Z. Drug Discov Today 26 289-295 (2021)
  2. Overcoming resistance in non-small-cell lung cancer: A practical lesson for the medicinal chemist. Ribaudo G, Zanforlin E, Zagotto G. Arch Pharm (Weinheim) 351 e1800037 (2018)
  3. Redox Regulation, Oxidative Stress, and Inflammation in Group 3 Pulmonary Hypertension. Rudyk O, Aaronson PI. Adv Exp Med Biol 1303 209-241 (2021)

Articles citing this publication (12)

  1. Editorial C797S Resistance: The Undruggable EGFR Mutation in Non-Small Cell Lung Cancer? Grabe T, Lategahn J, Rauh D. ACS Med Chem Lett 9 779-782 (2018)
  2. Water-Soluble Pristine C60 Fullerenes Inhibit Liver Fibrotic Alteration and Prevent Liver Cirrhosis in Rats. Kuznietsova H, Dziubenko N, Hurmach V, Chereschuk I, Motuziuk O, Ogloblya O, Prylutskyy Y. Oxid Med Cell Longev 2020 8061246 (2020)
  3. Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death. Iradyan M, Iradyan N, Hulin P, Hambardzumyan A, Gyulkhandanyan A, Alves de Sousa R, Hessani A, Roussakis C, Bollot G, Bauvais C, Sakanyan V. Cancers (Basel) 11 E1094 (2019)
  4. Leveraging Atropisomerism to Obtain a Selective Inhibitor of RET Kinase with Secondary Activities toward EGFR Mutants. Toenjes ST, Garcia V, Maddox SM, Dawson GA, Ortiz MA, Piedrafita FJ, Gustafson JL. ACS Chem Biol 14 1930-1939 (2019)
  5. How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study. E J, Liu Y, Guan S, Luo Z, Han F, Han W, Wang S, Zhang H. Molecules 25 E895 (2020)
  6. Icotinib, Almonertinib, and Olmutinib: A 2D Similarity/Docking-Based Study to Predict the Potential Binding Modes and Interactions into EGFR. Almalki FA, Shawky AM, Abdalla AN, Gouda AM. Molecules 26 6423 (2021)
  7. L718Q/V mutation in exon 18 of EGFR mediates resistance to osimertinib: clinical features and treatment. Li M, Qin J, Xie F, Gong L, Han N, Lu H. Discov Oncol 13 72 (2022)
  8. Anticancer activity, phytochemical investigation and molecular docking insights of Citrullus colocynthis (L.) fruits. Mandour YM, Refaat E, Hassanein HD. Sci Rep 13 20038 (2023)
  9. Molecular Targets in Lung Cancer: Study of the Evolution of Biomarkers Associated with Treatment with Tyrosine Kinase Inhibitors-Has NF1 Tumor Suppressor a Key Role in Acquired Resistance? Alen BO, Estévez-Pérez LS, Hermida-Romero MT, Reguera-Arias A, García-Campelo R, de la Torre-Bravos M, Concha Á. Cancers (Basel) 14 3323 (2022)
  10. New Cladiellin-Type Diterpenoids from the South China Sea Soft Coral Cladiella krempfi: Structures and Molecular Docking Analysis in EGFRs. Jin Y, Yao LG, Guo YW, Li XW. Mar Drugs 20 381 (2022)
  11. Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors. Damghani T, Wittlinger F, Beyett TS, Eck MJ, Laufer SA, Heppner DE. Methods Enzymol 685 171-198 (2023)
  12. Systematic analysis and molecular profiling of EGFR allosteric inhibitor cross-reactivity across the proto-oncogenic ErbB family kinases by integrating dynamics simulation, energetics calculation and biochemical assay. Ma Y, Qi B, Ning M, Zhang L, An Z, Zhao J. Eur Biophys J 51 283-295 (2022)


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