Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance. (1st January 2018)

• Record Type: Journal Article
• Authors: Fischer, Tim; Najjar, Abdulkarim; Totzke, Frank; Schächtele, Christoph; Sippl, Wolfgang; Ritter, Christoph; Hilgeroth, Andreas
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 33:Number 1(2018)
• Page Start: 1
• Page End: 8
• Publication Date: 2018-01-01
• Subjects: Benzo-anellated compounds -- protein kinase inhibitory activity -- biological activity; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2017.1370583
• Languages: English
• ISSNs: 1475-6366

Abstract

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-β 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-β inhibiting properties. We identified dual inhibitors of both EGFR and PDGFR-β in the nanomolar range which have been initially screened in cancer cell lines to prove a benefit of both EGFR and PDGFR-β inhibition.