Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor

Steffen Bugge; Svein Jacob Kaspersen; Synne Larsen; Unni Nonstad; Geir Bjørkøy; Eirik Sundby; Bård Helge Hoff

doi:10.1016/j.ejmech.2014.01.042

Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor

Eur J Med Chem. 2014 Mar 21:75:354-74. doi: 10.1016/j.ejmech.2014.01.042. Epub 2014 Jan 31.

Authors

Steffen Bugge¹, Svein Jacob Kaspersen², Synne Larsen³, Unni Nonstad⁴, Geir Bjørkøy⁵, Eirik Sundby⁶, Bård Helge Hoff⁷

Affiliations

¹ Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Steffen.Bugge@chem.ntnu.no.
² Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.Jacob.Kaspersen@chem.ntnu.no.
³ Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: synnelar@gmail.com.
⁴ Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, NO-7491 Trondheim, Norway. Electronic address: unni.nonstad@ntnu.no.
⁵ Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, NO-7491 Trondheim, Norway; Sør-Trøndelag University College, Erling Skjalgssons Gate 1, NO-7004 Trondheim, Norway. Electronic address: geir.bjorkoy@hist.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: 24556149
DOI: 10.1016/j.ejmech.2014.01.042

Abstract

Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.

Keywords: Benzylamine; EGFR-TK; Erlotinib; SAR; Suzuki-coupling; Thienopyrimidine.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Benzylamines / chemistry
Cell Line, Tumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Models, Molecular
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*

Substances

Antineoplastic Agents
Benzylamines
Protein Kinase Inhibitors
Pyrimidines
thienopyrimidine
benzylamine
ErbB Receptors