Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

By Wenjun Zhou, D. Ercan, Liang Chen, C. Yun, Danan Li, M. Capelletti, A. Cortot, L. Chirieac, Roxana E. Iacob, R. Padera and 5 more. Nature, 2009

979 citations recorded by the source corpus.

The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

Subfields: Molecular Biology, Organic Chemistry, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/7081a42352378570e23f6c58fd855d8e01c978db

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Citations in the corpus

Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy (2015, positive): “PC9GR was obtained by continuously exposing PC9 to increasing concentrations of gefitinib (Ercan et al., 2010), selecting for a T790M mutation in EGFR that renders it non-sensitive to gefitinib but still sensitive to the mutant selective EGFR TKI WZ4002 (Zhou et al., 2009).”
Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors (2016, positive): “Mutant-selective irreversible inhibitors, including the tool compound WZ4002 15 and and the clinical compounds osimertinib (AZD9291) 6,16 and rociletinib (CO-1686) 5 , are based on a pyrimidine scaffold, and also incorporate a Michael acceptor group that forms a covalent bond with Cys797 at the edge”
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors (2013, methodology): “Separate mouse models carrying both the T790M and L858R or Del19 have been characterized (14, 15); while these do not respond to erlotinib therapy, they do respond to the mutant specific irreversible EGFR inhibitor WZ4002 for several weeks before they acquire resistance through other mechanisms (16)”
Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition (2016, neutral): “The gene targets covered by this assay are as follows (exons): AKT1 (3), ALK (22, 23, 25), APC (16), BRAF (11, 15), CDH1 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16), CDKN2A (1, 2, 3), CTNNB1 (3), DDR2 (12, 13, 14, 15, 16, 17, 18), EGFR (7, 15, 18, 19, 20, 21), ERBB2 (10, 20), ESR1 (8), FB”
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer (2010, background): “Recently, a new compound, WZ4002 (Gatekeeper Pharmaceuticals), was discovered through screening different core chemical scaffolds for their ability to fit in the ATP-binding pocket of EGFR specifically in the presence of T790”
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors (2011, methodology): “Retroviral infection and culture of Ba/F3 cell were performed using previously described methods (18).”