A General Strategy for Creating "Inactive-Conformation" Abl Inhibitors

Barun Okram, Advait Nagle, Francisco J. Adrián, Christian Lee, Pingda Ren, Xia Wang, Taebo Sim, Yongping Xie, Xing Wang, Gang Xia, Glen Spraggon, Markus Warmuth, Yi Liu, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)


Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.

Original languageEnglish
Pages (from-to)779-786
Number of pages8
JournalChemistry and Biology
Issue number7
Publication statusPublished - 2006 Jul



ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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