title: Development of 'DFG-out' inhibitors of gatekeeper mutant kinases.
abstract: HG-7-85-01(22) and HG-7-86-01(26) are thiazolo[5,4-b]pyridine containing type II tyrosine kinase inhibitors with potent cellular activity against both wild-type and 'gatekeeper' mutant T315I- Bcr-Abl. Here we report on the 'hybrid design' concept and subsequent structure activity guided optimization efforts that resulted in the development of these inhibitors.
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Hwan Geun
authors: HG
authors: Choi
authors: Jianming
authors: J
authors: Zhang
authors: Ellen
authors: E
authors: Weisberg
authors: James D
authors: JD
authors: Griffin
authors: Taebo
authors: T
authors: Sim
authors: Nathanael S
authors: NS
authors: Gray
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D006860:Hydrogen Bonding; D051379:Mice; D009154:Mutation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: C552521:HG-7-85-01 compound; C576477:HG-7-86-01; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl