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Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-? related to anticancer drug resistance.

ABSTRACT: With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-? that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-anilino residue to evaluate their EGFR and PDGFR-? inhibiting properties. We identified dual inhibitors of both EGFR and PDGFR-? in the nanomolar range which have been initially screened in cancer cell lines to prove a benefit of both EGFR and PDGFR-? inhibition.

SUBMITTER: Fischer T

PROVIDER: S-EPMC6009873 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance.

Fischer Tim T Najjar Abdulkarim A Totzke Frank F Schächtele Christoph C Sippl Wolfgang W Ritter Christoph C Hilgeroth Andreas A

Journal of enzyme inhibition and medicinal chemistry 20181201 1

With ongoing resistance problems against the marketed EGFR inhibitors having a quinazoline core scaffold there is a need for the development of novel inhibitors having a modified scaffold and, thus, expected lower EGFR resistance problems. An additional problem concerning EGFR inhibitor resistance is an observed heterodimerization of EGFR with PDGFR-β that neutralises the sole inhibitor activity towards EGFR. We developed novel pyrimido[4,5-b]indoles with varied substitution patterns at the 4-an ...[more]

PMID: 29098884

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Project description:Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In EGFR-mutant non-small cell lung cancer with EGFR tyrosine kinase inhibitor (TKI) resistance (PC9-GR, HCC827-GR, and H1975-OR), OST inhibition maintained its ability to induce cell-cycle arrest and a proliferative block. Addition of NGI-1 to EGFR TKI treatment was synthetic lethal in cells resistant to gefitinib, erlotinib, or osimertinib. OST inhibition invariably disrupted EGFR N-linked glycosylation and reduced activation of receptors either with or without the T790M TKI resistance mutation. OST inhibition also dissociated EGFR signaling from other coexpressed receptors like MET via altered receptor compartmentalization. Translation of this approach to preclinical models was accomplished through synthesis and delivery of NGI-1 nanoparticles, confirmation of in vivo activity through molecular imaging, and demonstration of significant tumor growth delay in TKI-resistant HCC827 and H1975 xenografts. This therapeutic strategy breaks from kinase-targeted approaches and validates N-linked glycosylation as an effective target in tumors driven by glycoprotein signaling.Significance:EGFR-mutant NSCLC is incurable despite the marked sensitivity of these tumors to EGFR TKIs. These findings identify N-linked glycosylation, a posttranslational modification common to EGFR and other oncogenic signaling proteins, as an effective therapeutic target that enhances tumor responses for EGFR-mutant NSCLC. Cancer Res; 78(17); 5094-106. ©2018 AACR.

Dataset Information

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-? related to anticancer drug resistance.

Publications

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance.

Similar Datasets

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