Computational studies of potent covalent inhibitors on wild type or T790M/L858R mutant epidermal growth factor receptor

Yang, Zhilu; Yang, Hai‐Kui; Ai, Yangcheng; Zhang, Lishun; Li, Zhonghuang; Wan, Shanhe; Xu, Xuan; Zhang, Huiwu; Wu, Shaoyu; Zhang, Jiajie; Zhang, Tingting

doi:10.1016/j.ejps.2020.105463

Cited by 11 publications

(7 citation statements)

References 55 publications

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“…no. 62TK0PEC) according to the manufacturer’s instructions and previous studies. , Briefly, the compound, protein, Tk-substrate (an artificial substrate peptide), and ATP were diluted by kinase buffer [supplemented with 1 mM dithiothreitol (DTT) 5 mM MgCl 2 , and 1 mM MnCl 2 ]. The compound and EGFR (0.037 ng/μL) were first added to a 384-well plate.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

Yang,

Liu,

Wan

et al. 2024

J. Med. Chem.

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Based on the close relationship between programmed death protein ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) in glioblastoma (GBM), we designed and synthesized a series of small molecules as potential dual inhibitors of EGFR and PD-L1. Among them, compound EP26 exhibited the highest inhibitory activity against EGFR (IC50 = 37.5 nM) and PD-1/PD-L1 interaction (IC50 = 1.77 μM). In addition, EP26 displayed superior in vitro antiproliferative activities and in vitro immunomodulatory effects by promoting U87MG cell death in a U87MG/Jurkat cell coculture model. Furthermore, EP26 possessed favorable pharmacokinetic properties (F = 22%) and inhibited tumor growth (TGI = 92.0%) in a GBM mouse model more effectively than Gefitinib (77.2%) and NP19 (82.8%). Moreover, EP26 increased CD4+ cells and CD8+ cells in tumor microenvironment. Collectively, these results suggest that EP26 represents the first small-molecule-based PD-L1/EGFR dual inhibitor deserving further investigation as an immunomodulating agent for cancer treatment.

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Section: Methodsmentioning

confidence: 99%

Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

Yang,

Liu,

Wan

et al. 2024

J. Med. Chem.

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“…The Extra-Precision (XP) docking mode was considered in the docking process, and other parameters were set by default. The MD simulations performed by Amber12 program refer to our previous research [ 19 , 20 ], and the detailed method used is described in the Supplementary Materials .…”

Section: Methodsmentioning

confidence: 99%

A Novel and Highly Selective Epidermal Growth Factor Receptor Inhibitor, SMUZ106, for the Treatment of Glioblastoma

Jiang

Huang

et al. 2023

Pharmaceutics

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Targeting the epidermal growth factor receptor (EGFR) is one of the potential ways to treat glioblastoma (GBM). In this study, we investigate the anti-GBM tumor effects of the EGFR inhibitor SMUZ106 in both in vitro and in vivo conditions. The effects of SMUZ106 on the growth and proliferation of GBM cells were explored through MTT and clone formation experiments. Additionally, flow cytometry experiments were conducted to study the effects of SMUZ106 on the cell cycle and apoptosis of GBM cells. The inhibitory activity and selectivity of SMUZ106 to the EGFR protein were proved by Western blotting, molecular docking, and kinase spectrum screening methods. We also conducted a pharmacokinetic analysis of SMUZ106 hydrochloride following i.v. or p.o. administration to mice and assessed the acute toxicity level of SMUZ106 hydrochloride following p.o. administration to mice. Subcutaneous and orthotopic xenograft models of U87MG-EGFRvIII cells were established to assess the antitumor activity of SMUZ106 hydrochloride in vivo. SMUZ106 could inhibit the growth and proliferation of GBM cells, especially for the U87MG-EGFRvIII cells with a mean IC50 value of 4.36 μM. Western blotting analyses showed that compound SMUZ106 inhibits the level of EGFR phosphorylation in GBM cells. It was also shown that SMUZ106 targets EGFR and presents high selectivity. In vivo, the absolute bioavailability of SMUZ106 hydrochloride was 51.97%, and its LD50 exceeded 5000 mg/kg. SMUZ106 hydrochloride significantly inhibited GBM growth in vivo. Furthermore, SMUZ106 inhibited the activity of U87MG-resistant cells induced by temozolomide (TMZ) (IC50: 7.86 μM). These results suggest that SMUZ106 hydrochloride has the potential to be used as a treatment method for GBM as an EGFR inhibitor.

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“…The binding free energy (Δ G bind ) was calculated by using MM-GBSA − in Amber12. , We selected 1000 snapshots derived from the last 10 ns of MD trajectories to determine the Δ G bind . The details of the calculation can be seen in our previous study. , Δ G bind = G complex − false( italicG normalprotein + italicG normalcompound false) Covalent docking was performed using the CovDock module of the Schrödinger suite . The compound bound to the kinase covalently was predicted by the default protocol.…”

Section: Methodsmentioning

confidence: 99%

“…The ATP concentration was set at the respective K m value (27.71 μM for EGFR). Please refer to our previous research for more detailed methods. , We first added compounds to the 384-well plate, then added enzymes and incubated for 10 min before adding TK substrate and ATP. At this time, the 384-well plate was placed in an incubator at 37 °C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

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Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

Yang

et al. 2023

J. Chem. Inf. Model.

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Both reversible noncovalent inhibitors and irreversible covalent inhibitors targeting tyrosine kinases have their disadvantages. The reversible covalent inhibitors with electrophilic group cyanoacrylamide as warheads reacting with cysteine residues could solve the dilemmas. However, there are still several unresolved issues regarding the electrophilic groups. In this manuscript, a series of EGFR inhibitors with double electron-withdrawing substituents introduced into the C α position on the olefin bond were designed and synthesized. The binding structures and characteristics of inhibitors with the kinase in both the first noncovalent binding phase and the second covalent binding step were explored and combined with molecular docking and molecular dynamics simulations. Then, the reverse β-elimination reactions of the thiol-Michael adducts were investigated by applying density functional theory calculations. In addition, the effects of different electrophilic substituents of C α on the binding between the inhibitors and kinase were elucidated. The results suggested that the electrophilicity and size of the electronwithdrawing groups play an important role in the specific interactions during the reaction. The compounds with the electronwithdrawing groups that had medium electrostatic and steric complementarity to the kinase active site could cooperatively stabilize the complexes and showed relatively good potent activities in the kinase assay experiment. The mechanical and structural information in this study could enhance our understanding of the functioning of the electron-withdrawing groups in the covalent inhibitors. The results might help to design efficient cysteine targeting inhibitors in the future.

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Computational studies of potent covalent inhibitors on wild type or T790M/L858R mutant epidermal growth factor receptor

Cited by 11 publications

References 55 publications

Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

Discovery of Novel Small-Molecule-Based Potential PD-L1/EGFR Dual Inhibitors with High Druggability for Glioblastoma Immunotherapy

A Novel and Highly Selective Epidermal Growth Factor Receptor Inhibitor, SMUZ106, for the Treatment of Glioblastoma

Discovery and Computational Studies of Potent Covalent Kinase Inhibitors with α-Substituent Electrophiles Targeting Cysteine

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