Design and synthesis of a novel tyrosine kinase inhibitor template.
We report the design and synthesis of an insulin receptor kinase family-targeted inhibitor template using the inhibitor conformation observed in an IGF1R/inhibitor co-crystal complex by application of a novel molecular design approach that we have recently published. The synthesis of the template involves a one pot Opatz cyclization reaction that provides a versatile indole ester in good yields. We also developed the required chemistry to elaborate this template with additional substituents and have used this chemistry to prepare some initial compounds that show selective inhibition of anaplastic lymphoma kinase (ALK).
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105-3678, United States.
P
P
Jake Slavish
Qin
Q
Jiang
Xiaoli
X
Cui
Stephan W
SW
Morris
Thomas R
TR
Webb
D000077548:Anaplastic Lymphoma Kinase; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin