Structural basis of mutant-selectivity and drug-resistance related to CO-1686

Abstract

Non-small-cell lung cancers (NSCLCs) caused by activating mutations in the kinase domain of epidermal growth factor receptor (EGFR) initially respond to first-generation reversible drugs gefitinib and erlotinib. However, clinical efficacy is limited due to the development of drug-resistance that in more than half of the cases are driven by the secondary T790M mutation. CO-1686 is one of the third generation irreversible inhibitors that inhibits EGFR activating mutants, including those with concurrent T790M, while avoiding the off-target toxicity owing to inhibition of wild-type EGFR in treating EGFR mutation-positive NSCLCs. Despite the remarkable success, the experimentally determined structure of this agent in complex with EGFR T790M remains unknown. In this study, we determined crystal structures of EGFR T790M or L858R mutants covalently bound by CO-1686. Based on these structural data, we can explain why CO-1686 irreversibly inhibits EGFR and selectively prefers T790M, which may help improving this or similar compounds, and explain why EGFR L718Q and L844V mutations incur resistance to this agent.

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib

“…It has been recently proposed that the main effect of the replacement of Leu718 with Gln718 could be to disrupt the beneficial hydrophobic/steric interactions involving the methoxyphenyl moiety 38 of third generation EGFR inhibitors ( Fig. 1 ) and thus to hamper the formation of the non-covalent complex through a significant reduction of inhibitor affinity.…”

Structural insights into drug development strategy targeting EGFR T790M/C797S

“…The newly developed non-covalent inhibitor SKLB(5), however, makes full use of the hydrophobic clamp due to the additional cyclopentyl rings attached to the core scaffold of the compounds (shown by red arrows in Figure 2B, 2E ), which participates in direct interactions with Leu 844, Leu 718 and Val 726 side-chains. Interestingly, it was found in the structural analysis that the covalent inhibitor WZ4002, CO-1686 and AZD9291 also partly rely on the hydrophobic clamp to bind to EGFR, as 4-phenoxyl in WZ4002, 4-aniline in CO-1686 and 1-methyl-1 H -indole in AZD9291 (Figure 1 ) directly interact with the hydrophobic residues (shown by red arrows in Figure 2K, 2M, 2N ; also see Supplementary Figure 4 ) [ 14 , 30 , 31 ]. This observation can well explain the interesting finding that although L718Q and L844V led to resistance to WZ4002, they remained sensitive to quinazoline-based irreversible EGFR inhibitors afatinib and neratinib (which are similar to gefitinib or lapatinib, see Figure 1 ) [ 20 ].…”

Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer

“…Molecular docking calculations were performed with the software AutoDock Vina (version 1.1.2) for modeling the binding modes and assessing the interaction energies of the studied compounds as ligands for several enzymes. The three‐dimensional coordinates of the proteins were obtained from the RCSB Protein Data Bank (PDB IDs: 3PP0 (HER2), 5XDL (HER1), 3SDK (20S proteasome), 4AG8 (VEGFR2), 4XV2 (BRAF), 4LVT (Bcl‐2), and 5X5D (hTS)). Chain A of HER2, HER1, VEGFR2, BRAF, Bcl‐2 and hTS, and chains K (β5 subunit) and L (β6 subunit) of 20S proteasome were selected as target templates for the docking computations.…”