2. Academic Validation
  3. Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)

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

  • ACS Med Chem Lett. 2022 Nov 10;13(12):1856-1863. doi: 10.1021/acsmedchemlett.2c00213.
David E Heppner 1 2,  Florian Wittlinger 3,  Tyler S Beyett 4 5,  Tatiana Shaurova 2,  Daniel A Urul 6,  Brian Buckley 7,  Calvin D Pham 1,  Ilse K Schaeffner 4 5,  Bo Yang 4 5,  Blessing C Ogboo 1,  Earl W May 6,  Erik M Schaefer 6,  Michael J Eck 4 5,  Stefan A Laufer 3 8 9,  Pamela A Hershberger 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, United States.
  • 2 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 6 AssayQuant Technologies, Inc., 260 Cedar Hill St., Marlboro, Massachusetts 01752, United States.
  • 7 Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, United States.
  • 8 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany.
  • 9 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
PMID: 36518696 DOI: 10.1021/acsmedchemlett.2c00213
Abstract

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.

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