Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones

Thomas Beckers; Andreas Sellmer; Emerich Eichhorn; Herwig Pongratz; Christoph Schächtele; Frank Totzke; Gerhard Kelter; Rebekka Krumbach; Heinz-Herbert Fiebig; Frank-D Böhmer; Siavosh Mahboobi

doi:10.1016/j.bmc.2011.11.023

Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones

Bioorg Med Chem. 2012 Jan 1;20(1):125-36. doi: 10.1016/j.bmc.2011.11.023. Epub 2011 Nov 20.

Authors

Thomas Beckers¹, Andreas Sellmer, Emerich Eichhorn, Herwig Pongratz, Christoph Schächtele, Frank Totzke, Gerhard Kelter, Rebekka Krumbach, Heinz-Herbert Fiebig, Frank-D Böhmer, Siavosh Mahboobi

Affiliation

¹ Department of Pharmaceutical Chemistry I, University of Regensburg, D-93040 Regensburg, Germany.

PMID: 22169601
DOI: 10.1016/j.bmc.2011.11.023

Abstract

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC(50) values ranging form 0.3-1μM for compound 42, and 0.1-0.3μM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / pharmacology
Phosphorylation / drug effects
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology
Structure-Activity Relationship

Substances

(4-(3-chloro-4-fluorophenylamino)thieno(2,3-d)pyrimidin-6-yl)(5-hydroxy-1H-indol-2-yl)methanone
(4-(3-chlorophenylamino)thieno(2,3-d)pyrimidin-6-yl)(1H-indol-2-yl)methanone
Antineoplastic Agents
Indoles
Pyrimidines
Quinazolines
ErbB Receptors
pyrimidine