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  3. Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties

Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties

  • Eur J Med Chem. 2016 Jan 1:107:255-74. doi: 10.1016/j.ejmech.2015.11.012.
Steffen Bugge 1,  Audun Formo Buene 2,  Nathalie Jurisch-Yaksi 3,  Ingri Ullestad Moen 4,  Ellen Martine Skjønsfjell 5,  Eirik Sundby 6,  Bård Helge Hoff 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: steffen.bugge@ntnu.no.
  • 2 Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: audun.f.buene@ntnu.no.
  • 3 Kavli Institute for Systems Neuroscience and Center for Neural Computation, Norwegian University of Science and Technology, Olav Kyrres gate 9, MTFS, NO-7491 Trondheim, Norway. Electronic address: nathalie.jurisch-yaksi@ntnu.no.
  • 4 Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: ingriumoen@gmail.com.
  • 5 Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: ellenmsk@stud.ntnu.no.
  • 6 Sør-Trøndelag University College, E.C. Dahls gate 2, NO-7004 Trondheim, Norway. Electronic address: Eirik.Sundby@hist.no.
  • 7 Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.
PMID: 26599532 DOI: 10.1016/j.ejmech.2015.11.012
Abstract

Thieno[2,3-d]pyrimidines are attractive derivatives for Cancer treatment, among Others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human Cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents.

Keywords

ADME; EGFR; Erlotinib; Gefitinib; Structure–activity relationship (SAR); Thieno[2,3-d]pyrimidine; Zebrafish.

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