Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein

Sharifi, Amirhossein; Bagherzadeh, Kowsar; Golestanian, Sahand; Amanlou, Massoud

doi:10.2174/1386207319666160115132121

Cited by 2 publications

(1 citation statement)

References 47 publications

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“…The pyrimidine moiety of the BBT-176 core structure forms two conventional hydrogen bonds with Met793 of the hinge region, the piperidine moiety forms salt bridges with Glu904 and Asp800, and multiple hydrophobic interactions of aromatic rings occur. The differences in spatial position of Lys745, Asp855, and Gly857 are observed in the active and inactive kinase domain ( 29 ). In the inactive state of EGFR, the lysine forms a salt bridge with Asp855 of the DFG motif and with Glu762 of the αC-helix.…”

Section: Resultsmentioning

confidence: 99%

BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer

Lim,

Fujino,

Kim

et al. 2023

Clinical Cancer Research

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Purpose: Resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors including osimertinib arises in part from the C797S mutation in EGFR. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting C797S mutation. Patients and Methods: Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells and patient-derived xenografts expressing mutant EGFRs were used to test the inhibitory potency and the efficacy of BBT-176 both in vitro and in vivo. Patient cases are derived from an ongoing phase 1 clinical trial (NCT04820023). Results: The half maximal inhibitory concentration (IC50) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S protein were measured at 4.36, 1.79 and 5.35 nM, respectively (vs. 304.39, 124.82, and 573.72 nM, for osimertinib). IC50 values of BBT‑176 against Ba/F3 cells expressing EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, EGFR L858R/C797S, and EGFR L858R/T790M/C797S were 42, 49, 183 and 202 nM, respectively (vs 869, 1134, 2799, and 2685 nM for osimertinib). N-Ethyl-N-nitrosourea (ENU) mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the EGFR gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT‑176 effectively suppressed the growth of BBT-176-resistant clones. BBT‑176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients from harboring EGFR 19Del/T790M/C797S in blood showed tumor shrinkage and radiological improvements. Conclusions: BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKIs.

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Section: Resultsmentioning

confidence: 99%

BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer

Lim,

Fujino,

Kim

et al. 2023

Clinical Cancer Research

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Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy

et al. 2017

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Cancer cells are described with features of uncontrolled growth, invasion and metastasis. The epidermal growth factor receptor subfamily of tyrosine kinases (EGFR-TK) plays a crucial regulatory role in the control of cellular proliferation and progression of various cancers. Therefore, its inhibition might lead to the discovery of a new generation of anticancer drugs. In the present study, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK. Selected compounds were examined for their anticancer activity against the Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line which overexpresses EGFR using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay. Compounds 1 and 2, with an isoindoline-1-one core, induced significant inhibition of breast cancer cells proliferation with IC[Formula: see text] values 327 and 370 nM, respectively.

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Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein

Cited by 2 publications

References 47 publications

BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer

BBT-176, a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non–Small Cell Lung Cancer

Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy

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