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Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)

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    Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)
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    • David E. Heppner*
      David E. Heppner
      Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
      Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States
      *Phone: (716) 645-5133; Email: [email protected]
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    • Florian Wittlinger
      Florian Wittlinger
      Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
      More by Florian Wittlinger
      Orcidhttps://orcid.org/0000-0001-9028-2109
    • Tyler S. Beyett
      Tyler S. Beyett
      Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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    • Tatiana Shaurova
      Tatiana Shaurova
      Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States
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    • Daniel A. Urul
      Daniel A. Urul
      AssayQuant Technologies, Inc., 260 Cedar Hill St., Marlboro, Massachusetts 01752, United States
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    • Brian Buckley
      Brian Buckley
      Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States
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    • Calvin D. Pham
      Calvin D. Pham
      Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
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    • Ilse K. Schaeffner
      Ilse K. Schaeffner
      Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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    • Bo Yang
      Bo Yang
      Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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    • Blessing C. Ogboo
      Blessing C. Ogboo
      Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States
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    • Earl W. May
      Earl W. May
      AssayQuant Technologies, Inc., 260 Cedar Hill St., Marlboro, Massachusetts 01752, United States
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    • Erik M. Schaefer
      Erik M. Schaefer
      AssayQuant Technologies, Inc., 260 Cedar Hill St., Marlboro, Massachusetts 01752, United States
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    • Michael J. Eck
      Michael J. Eck
      Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States
      Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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    • Stefan A. Laufer
      Stefan A. Laufer
      Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
      Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany
      Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany
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      Orcidhttps://orcid.org/0000-0001-6952-1486
    • Pamela A. Hershberger
      Pamela A. Hershberger
      Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States
      More by Pamela A. Hershberger
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2022, 13, 12, 1856–1863
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    https://doi.org/10.1021/acsmedchemlett.2c00213
    Published November 10, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand the nature of lazertinib inhibition, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally related EGFR TKIs. We observe that lazertinib binds EGFR with a distinctive pyrazole moiety enabling hydrogen bonds and van der Waals interactions facilitated through hydrophilic amine and hydrophobic phenyl groups, respectively. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent HER2. The molecular basis for lazertinib inhibition of EGFR reported here highlights previously unexplored binding interactions leading to improved medicinal chemistry properties compared to clinically approved osimertinib (AZD9291) and offers novel strategies for structure-guided design of tyrosine kinase inhibitors.

    Copyright © 2022 American Chemical Society

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    This article is cited by 32 publications.

    1. David E. Heppner. Ascertaining a Structural Basis in Drug Discovery and Development. Journal of Medicinal Chemistry 2025, 68 (5) , 4991-4995. https://doi.org/10.1021/acs.jmedchem.5c00326
    2. Samuel E. Dalton, Ornella Di Pietro, Elisabeth Hennessy. A Medicinal Chemistry Perspective on FDA-Approved Small Molecule Drugs with a Covalent Mechanism of Action. Journal of Medicinal Chemistry 2025, 68 (3) , 2307-2313. https://doi.org/10.1021/acs.jmedchem.4c02661
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    4. David E. Heppner, (J. Med. Chem. Early Career Board)Blessing C. Ogboo, Daniel A. Urul, Earl W. May, Erik M. Schaefer, Andrew S. Murkin, Matthias Gehringer (J. Med. Chem. Editorial Advisory Board). Demystifying Functional Parameters for Irreversible Enzyme Inhibitors. Journal of Medicinal Chemistry 2024, 67 (17) , 14693-14696. https://doi.org/10.1021/acs.jmedchem.4c01721
    5. Kristopher W. Hoyt, Daniel A. Urul, Blessing C. Ogboo, Florian Wittlinger, Stefan A. Laufer, Erik M. Schaefer, Earl W. May, David E. Heppner. Pitfalls and Considerations in Determining the Potency and Mutant Selectivity of Covalent Epidermal Growth Factor Receptor Inhibitors. Journal of Medicinal Chemistry 2024, 67 (1) , 2-16. https://doi.org/10.1021/acs.jmedchem.3c01502
    6. Berkant Kurban, Begüm Nurpelin Sağlık, Derya Osmaniye, Serkan Levent, Yusuf Özkay, Zafer Asım Kaplancıklı. Synthesis and Anticancer Activities of Pyrazole–Thiadiazole-Based EGFR Inhibitors. ACS Omega 2023, 8 (34) , 31500-31509. https://doi.org/10.1021/acsomega.3c04635
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    12. Jinyong Kim, Sehhoon Park, Bo Mi Ku, Myung‐Ju Ahn. Updates on the treatment of epidermal growth factor receptor‐mutant non–small cell lung cancer. Cancer 2025, 131 (S1) https://doi.org/10.1002/cncr.35778
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    18. Kamel Metwally, Nader E. Abo-Dya. Pyrrolo[2,3-D]Pyrimidines as EGFR and VEGFR Kinase Inhibitors: A Comprehensive SAR Review. Current Medicinal Chemistry 2024, 31 (36) , 5918-5936. https://doi.org/10.2174/0929867331666230815115111
    19. Byoung C. Cho, Shun Lu, Enriqueta Felip, Alexander I. Spira, Nicolas Girard, Jong-Seok Lee, Se-Hoon Lee, Yurii Ostapenko, Pongwut Danchaivijitr, Baogang Liu, Adlinda Alip, Ernesto Korbenfeld, Josiane Mourão Dias, Benjamin Besse, Ki-Hyeong Lee, Hailin Xiong, Soon-Hin How, Ying Cheng, Gee-Chen Chang, Hiroshige Yoshioka, James C.-H. Yang, Michael Thomas, Danny Nguyen, Sai-Hong I. Ou, Sanjay Mukhedkar, Kumar Prabhash, Manolo D’Arcangelo, Jorge Alatorre-Alexander, Juan C. Vázquez Limón, Sara Alves, Daniil Stroyakovskiy, Marina Peregudova, Mehmet A.N. Şendur, Ozan Yazici, Raffaele Califano, Vanesa Gutiérrez Calderón, Filippo de Marinis, Antonio Passaro, Sang-We Kim, Shirish M. Gadgeel, John Xie, Tao Sun, Melissa Martinez, Mariah Ennis, Elizabeth Fennema, Mahesh Daksh, Dawn Millington, Isabelle Leconte, Ryota Iwasawa, Patricia Lorenzini, Mahadi Baig, Sujay Shah, Joshua M. Bauml, S. Martin Shreeve, Seema Sethi, Roland E. Knoblauch, Hidetoshi Hayashi. Amivantamab plus Lazertinib in Previously Untreated EGFR -Mutated Advanced NSCLC. New England Journal of Medicine 2024, 391 (16) , 1486-1498. https://doi.org/10.1056/NEJMoa2403614
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    31. Yichao Kong, Caihong Jiang, Guifeng Wei, Kai Sun, Ruijie Wang, Ting Qiu. Small Molecule Inhibitors as Therapeutic Agents Targeting Oncogenic Fusion Proteins: Current Status and Clinical. Molecules 2023, 28 (12) , 4672. https://doi.org/10.3390/molecules28124672
    32. Tahereh Damghani, Florian Wittlinger, Tyler S. Beyett, Michael J. Eck, Stefan A. Laufer, David E. Heppner. Structural elements that enable specificity for mutant EGFR kinase domains with next-generation small-molecule inhibitors. 2023, 171-198. https://doi.org/10.1016/bs.mie.2023.03.013
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2022, 13, 12, 1856–1863
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.2c00213
    Published November 10, 2022
    Copyright © 2022 American Chemical Society
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