Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors

Waterson, Alex G.; Petrov, Kimberly G.; Hornberger, Keith R.; Hubbard, Robert D.; Sammond, Douglas M.; Smith, Stephon C.; Dickson, Hamilton D.; Caferro, Thomas R.; Hinkle, Kevin W.; Stevens, Kirk L.; Dickerson, Scott H.; Rusnak, David W.; Spehar, Glenn; Wood, Edgar R.; Griffin, Robert J.; Uehling, David

doi:10.1016/j.bmcl.2009.01.080

Cited by 34 publications

(14 citation statements)

References 22 publications

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“…A chemically diverse set of 60 EGFR TK inhibitors [35][36][37] with IC 50 values spanning a wide range from 0.38 nM to 17900 nM were taken for 3D QSAR model development. The molecules were rationally divided into training and test sets of 26 and 34 compounds respectively ( Figure 2; Tables 1 and 2) using the Catalyst/Discovery Studio-based standard guidelines.…”

Section: Selection Of Moleculesmentioning

confidence: 99%

Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Gupta¹,

Bhunia²,

Balaramnavar³

et al. 2011

SAR and QSAR in Environmental Research

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A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r(training) = 0.89, r(test) = 0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.

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Section: Selection Of Moleculesmentioning

confidence: 99%

Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Gupta¹,

Bhunia²,

Balaramnavar³

et al. 2011

SAR and QSAR in Environmental Research

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“…Historical tyrosine kinase inhibitor lead discovery efforts have led to many quinazoline scaffold replacements in cancer chemotherapy discovery. 18-21 GW837016X ( 3 ) possesses a related core scaffold and was also found to be potent against T. brucei . It therefore seemed appropriate to utilize the thieno[3,2- d ]pyrimidine (and the regioisomeric thieno[2,3- d ]pyrimidine) scaffolds to launch a crossover SAR study, preparing analogs matched to those quinazoline-based inhibitors previously described 7 (denoted in this article as 4b-m , Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

et al. 2015

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Target repurposing is a proven method for finding new lead compounds that target Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas’ disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.

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“…Tumour growth arrest by lapatinib was shown in human tumour xenografts [142], and the compound was approved for the treatment of breast cancer in 2007. Other groups have also investigated dual Erb-2/EGFR inhibitors [119,139].…”

Section: The Importance Of Determining Selectivitymentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

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Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

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Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors

Cited by 34 publications

References 22 publications

Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Pharmacophore modelling, molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

Measuring and interpreting the selectivity of protein kinase inhibitors

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