title: Design and combinatorial synthesis of a novel kinase-focused library using click chemistry-based fragment assembly.
abstract: Fragment-based lead discovery is a new approach for lead generation that has emerged in the past decade. Because the initial fragments identified in the fragment screening typically show weak binding affinity, an intensive medicinal chemistry effort would be required to grow initial fragments into a potential lead compound. Here we demonstrate a kinase focused evolved fragment (KFEF) library, constructed by click chemistry-based fragment assembly, that is a valuable source of kinase inhibitors. This combinatorial assembly of two fragments, kinase-privileged alkyne fragments and diversified azide fragments, by two cycloaddition reactions shows a unique potential for the one-step synthesis of structurally diverse evolved fragments. The screening of this triazole-based KFEF library allowed the rapid identification of potent lead candidates for FLT3 and GSK3β kinase.
authors: Drug Discovery Research, Carna Biosciences, Inc., 3rd Floor, BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. takayuki.irie@carnabio.com
authors: Takayuki
authors: T
authors: Irie
authors: Ikuo
authors: I
authors: Fujii
authors: Masaaki
authors: M
authors: Sawa
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D057930:Click Chemistry / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D014230:Triazoles / Q000737:chemistry; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014230:Triazoles; D000255:Adenosine Triphosphate; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D038362:Glycogen Synthase Kinase 3