Potent and selective EGFR inhibitors based on 5-aryl-7H-pyrrolopyrimidin-4-amines

Ann Christin Reiersølmoen; Thomas Ihle Aarhus; Sarah Eckelt; Kristin Gabestad Nørsett; Eirik Sundby; Bård Helge Hoff

doi:10.1016/j.bioorg.2019.102918

Potent and selective EGFR inhibitors based on 5-aryl-7H-pyrrolopyrimidin-4-amines

Bioorg Chem. 2019 Jul:88:102918. doi: 10.1016/j.bioorg.2019.102918. Epub 2019 Apr 11.

Authors

Ann Christin Reiersølmoen¹, Thomas Ihle Aarhus², Sarah Eckelt³, Kristin Gabestad Nørsett⁴, Eirik Sundby⁵, Bård Helge Hoff⁶

Affiliations

¹ Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway. Electronic address: Ann.C.Reiersolmoen@ntnu.no.
² Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway; Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway. Electronic address: Thomas.Aarhus@ntnu.no.
³ Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway; Institute of Organic Chemistry, Universität Hamburg, Welckerstrasse 8, 201354 Hamburg, Germany.
⁴ Department of Biomedical Laboratory Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway; Department of Computer Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway. Electronic address: Kristin.Norsett@ntnu.no.
⁵ Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway. Electronic address: Eirik.Sundby@ntnu.no.
⁶ Department of Chemistry, Norwegian University of Science and Technology (NTNU), NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.

PMID: 30999245
DOI: 10.1016/j.bioorg.2019.102918

Abstract

The epidermal growth factor receptor represents an important target in cancer therapy, and low molecular weight inhibitors based on quinazolines have reached the marked. Herein we report on a new scaffold, 5-aryl-7H-pyrrolo[2,3-d]pyrimidin-4-amines, and show that when employing (S)-phenylglycinol as C-4 substituent, potent inhibitors can be made. The two most active inhibitors have suitable druglike properties, were equipotent with Erlotinib in Ba/F3 cell studies, and showed lower cross reactivity than Erlotinib in a panel of 50 kinases.

Keywords: (S)-phenylglycinol; Chiral drug; EGFR; Erlotinib; Kinase; Pyrrolopyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Cell Line
Cell Proliferation / drug effects
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Erlotinib Hydrochloride / pharmacology
Mice
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / metabolism
Pyrroles / pharmacology*

Substances

Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Erlotinib Hydrochloride
ErbB Receptors