Structure Defines Function: Clinically Relevant Mutations in ErbB Kinases

Abstract

The ErbB receptor tyrosine kinase family members EGFR (epidermal growth factor receptor) and Her2 are among the prominent mutated oncogenic drivers of non-small cell lung cancer (NSCLC). Their importance in proliferation, apoptosis, and cell death ultimately renders them hot targets in cancer therapy. Small-molecule tyrosine kinase inhibitors seem well suited to be tailor-made therapeutics for EGFR mutant NSCLC; however, drug resistance mutations limit their success. Against this background, the elucidation and visualization of the three-dimensional structure of cancer-related kinases provide valuable insights into their molecular functions. This field has undergone a revolution because X-ray crystal structure determinations aided structure-based drug design approaches and clarified the effect of activating and resistance-conferring mutations. Here, we present an overview of important mutations affecting EGFR and Her2 and highlight their influence on the kinase domain conformations and active site accessibility.

Insight into the Therapeutic Selectivity of the Irreversible EGFR Tyrosine Kinase Inhibitor Osimertinib through Enzyme Kinetic Studies

“…Osimertinib employs an anilinopyrimidine core that makes two H-bonding interactions with the backbone of Met793, and an indole side chain that forms van der Waals interactions with various hydrophobic side chains from the P-loop, to allow the indole ring to point away from Thr790, leaving the space between Lys745 and Thr790 largely unoccupied (Figure A). However, the quinazoline-based first- and second-generation EGFR TKIs bind to WT EGFR in an extended conformation, with the substituted benzene ring positioned between Lys745 and Thr790 (Figure B). , On the basis of these crystal structures, the T790M mutation is more likely to disrupt the binding of first- and second-generation EGFR tyrosine kinase inhibitors due to steric clash but allows the Met790 side chain to make favorable hydrophobic interactions with the edge of the pyrimidine-indole ring of osimertinib, which likely confers the decreased off rate of osimertinib from the reversible EI complex with L858R/T790M EGFR. This is in broad agreement with the proposed T790M mutant selectivity mechanism for WZ4002, an earlier example of a third-generation EGFR TKI, and a reversible EGFR inhibitor using the osimertinib scaffold with a chlorine-substituted pyrimidine ring …”

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

“…Although no one succeed to gain crystal structures of EGFR-Del19 mutants, recent in silico molecular dynamics (MD) simulations revealed that Del19 mutations inferred that the reduced length and flexibility of N-terminal portion of aC-helix locks the helix αC-in state and prohibits transition to the inactive conformation. The EGFR structure (PDB IB: 1M17) is reported as a similar αC-helix-in structure to that of Del19 by MD simulation (44), and so we additionally superimposed our crystal structure (PDB ID: 6LUB) with this crystal structure (PDB ID: 1M17). As shown in revised Supplementary Fig.…”

Targeting Her2-insYVMA with Covalent Inhibitors—A Focused Compound Screening and Structure-Based Design Approach

“…About 80% of mutations that occur in Her2 are insertions that affect the beginning of the helix αC. , Most frequently found was the A775_G776insYVMA mutation that results in duplication of the YVMA motif (Figures A and S1). An accepted theory is that mutations in exon 20 induce a stabilized active conformation of the regulatory helix, thereby increasing the kinase activity which finally results in the onset of the RAS–RAF–MEK–ERK pathway that regulates cell proliferation and survival. , Moreover, signaling through amplified Her2 has been reported to be a mechanism of resistance toward the treatment of mutant EGFR with small-molecule tyrosine kinase inhibitors (TKIs) . Afatinib ( 1 ), , poziotinib, − dacomitinib, , neratinib ( 2 ), − and lapatinib ( 3 ) have been evaluated as TKIs targeting Her2.…”