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Structural pharmacological studies on EGFR T790M/C797S.

Kong LL, Ma R, Yao MY, Yan XE, Zhu SJ, Zhao P, Yun CH
Biochem Biophys Res Commun 488 266-272 (2017)
Cited: 11 times
EuropePMC logo PMID: 28456628

Abstract

Drug-resistance is a major challenge in targeted therapy of EGFR mutated non-small cell lung cancers (NSCLCs). The third-generation irreversible inhibitors such as AZD9291, CO-1686 and WZ4002 can overcome EGFR T790M drug-resistance mutant through covalent binding through Cys 797, but ultimately lose their efficacy upon emergence of the new mutation C797S. To develop new reversible inhibitors not relying on covalent binding through Cys 797 is therefore urgently demanded. Gö6976 is a staurosporine-like reversible inhibitor targeting T790M while sparing the wild-type EGFR. In the present work, we reported the complex crystal structures of EGFR T790M/C797S + Gö6976 and T790M + Gö6976, along with enzyme kinetic data of EGFR wild-type, T790M and T790M/C797S. These data showed that the C797S mutation does not significantly alter the structure and function of the EGFR kinase, but increases the local hydrophilicity around residue 797. The complex crystal structures also elucidated the detailed binding mode of Gö6976 to EGFR and explained why this compound prefers binding to T790M mutant. These structural pharmacological data would facilitate future drug development studies.

Reviews - 5xgn mentioned but not cited (1)

  1. Structure-Activity Relationship Studies Based on Quinazoline Derivatives as EGFR Kinase Inhibitors (2017-Present). Șandor A, Ionuț I, Marc G, Oniga I, Eniu D, Oniga O. Pharmaceuticals (Basel) 16 534 (2023)

Articles - 5xgn mentioned but not cited (1)

  1. Identification of novel bioactive molecules from garlic bulbs: A special effort to determine the anticancer potential against lung cancer with targeted drugs. Padmini R, Uma Maheshwari V, Saravanan P, Woo Lee K, Razia M, Alwahibi MS, Ravindran B, Soliman Elshikh M, Ock Kim Y, Kim H, Kim HJ. Saudi J Biol Sci 27 3274-3289 (2020)


Reviews citing this publication (2)

  1. [Acquired Drug Resistance Mechanism of Osimertinib in the Targeted Therapy of Non-small Cell Lung Cancer]. Zhao Z, Ni Y, Li L, Xin T. Zhongguo Fei Ai Za Zhi 23 274-281 (2020)
  2. Molecular tumour boards - current and future considerations for precision oncology. Tsimberidou AM, Kahle M, Vo HH, Baysal MA, Johnson A, Meric-Bernstam F. Nat Rev Clin Oncol 20 843-863 (2023)

Articles citing this publication (7)

  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. Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer. Little AC, Hristova M, van Lith L, Schiffers C, Dustin CM, Habibovic A, Danyal K, Heppner DE, Lin MJ, van der Velden J, Janssen-Heininger YM, van der Vliet A. Sci Rep 9 4844 (2019)
  3. Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy. Lu X, Zhang T, Zhu SJ, Xun Q, Tong L, Hu X, Li Y, Chan S, Su Y, Sun Y, Chen Y, Ding J, Yun CH, Xie H, Ding K. ACS Med Chem Lett 9 1123-1127 (2018)
  4. Case Reports Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature. Klempner SJ, Mehta P, Schrock AB, Ali SM, Ou SI. Lung Cancer (Auckl) 8 241-247 (2017)
  5. Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S. Lategahn J, Keul M, Klövekorn P, Tumbrink HL, Niggenaber J, Müller MP, Hodson L, Flaßhoff M, Hardick J, Grabe T, Engel J, Schultz-Fademrecht C, Baumann M, Ketzer J, Mühlenberg T, Hiller W, Günther G, Unger A, Müller H, Heimsoeth A, Golz C, Blank-Landeshammer B, Kollipara L, Zahedi RP, Strohmann C, Hengstler JG, van Otterlo WAL, Bauer S, Rauh D. Chem Sci 10 10789-10801 (2019)
  6. Computational modeling of novel quinazoline derivatives as potent epidermal growth factor receptor inhibitors. Ibrahim MT, Uzairu A, Uba S, Shallangwa GA. Heliyon 6 e03289 (2020)
  7. 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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