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Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors.

Heppner DE, Günther M, Wittlinger F, Laufer SA, Eck MJ
J Med Chem 63 4293-4305 (2020)
Related entries: 6v5n, 6v5p, 6v66, 6v6k, 6v6o, 6vh4, 6vhn

Cited: 12 times
EuropePMC logo PMID: 32243152

Abstract

Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "αC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.

Articles - 6vhp mentioned but not cited (1)

  1. Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors. Heppner DE, Günther M, Wittlinger F, Laufer SA, Eck MJ. J Med Chem 63 4293-4305 (2020)


Reviews citing this publication (2)

  1. A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer. Heppner DE, Eck MJ. Protein Sci 30 1535-1553 (2021)
  2. Imidazole: Synthesis, Functionalization and Physicochemical Properties of a Privileged Structure in Medicinal Chemistry. Tolomeu HV, Fraga CAM. Molecules 28 838 (2023)

Articles citing this publication (9)

  1. Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer. Eno MS, Brubaker JD, Campbell JE, De Savi C, Guzi TJ, Williams BD, Wilson D, Wilson K, Brooijmans N, Kim J, Özen A, Perola E, Hsieh J, Brown V, Fetalvero K, Garner A, Zhang Z, Stevison F, Woessner R, Singh J, Timsit Y, Kinkema C, Medendorp C, Lee C, Albayya F, Zalutskaya A, Schalm S, Dineen TA. J Med Chem 65 9662-9677 (2022)
  2. Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448). Heppner DE, Wittlinger F, Beyett TS, Shaurova T, Urul DA, Buckley B, Pham CD, Schaeffner IK, Yang B, Ogboo BC, May EW, Schaefer EM, Eck MJ, Laufer SA, Hershberger PA. ACS Med Chem Lett 13 1856-1863 (2022)
  3. Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/PI3K/AKT/mTOR Signaling Cascades. Shawish I, Barakat A, Aldalbahi A, Malebari AM, Nafie MS, Bekhit AA, Albohy A, Khan A, Ul-Haq Z, Haukka M, de la Torre BG, Albericio F, El-Faham A. ACS Omega 7 24858-24870 (2022)
  4. Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. Wittlinger F, Heppner DE, To C, Günther M, Shin BH, Rana JK, Schmoker AM, Beyett TS, Berger LM, Berger BT, Bauer N, Vasta JD, Corona CR, Robers MB, Knapp S, Jänne PA, Eck MJ, Laufer SA. J Med Chem 65 1370-1383 (2022)
  5. "From molecular to clinic": The pivotal role of CDC42 in pathophysiology of human papilloma virus related cancers and a correlated sensitivity of afatinib. Wei E, Li J, Anand P, French LE, Wattad A, Clanner-Engelshofen B, Reinholz M. Front Immunol 14 1118458 (2023)
  6. Discovery of Putative Dual Inhibitor of Tubulin and EGFR by Phenotypic Approach on LASSBio-1586 Homologs. Barbosa G, Gelves LGV, Costa CMX, Franco LS, Lima JAL, Aparecida-Silva C, Teixeira JD, Mermelstein CDS, Barreiro EJ, Lima LM. Pharmaceuticals (Basel) 15 913 (2022)
  7. Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents. Arafet K, Scalvini L, Galvani F, Martí S, Moliner V, Mor M, Lodola A. J Chem Inf Model 63 1301-1312 (2023)
  8. Addressing the Osimertinib Resistance Mutation EGFR-L858R/C797S with Reversible Aminopyrimidines. Grabe T, Jeyakumar K, Niggenaber J, Schulz T, Koska S, Kleinbölting S, Beck ME, Müller MP, Rauh D. ACS Med Chem Lett 14 591-598 (2023)
  9. 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)


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