6I5H

Crystal structure of CLK1 in complex with furanopyrimidin VN412

Summary for 6I5H

• Entry DOI: 10.2210/pdb6i5h/pdb
• Descriptor: Dual specificity protein kinase CLK1, 1,2-ETHANEDIOL, GLYCEROL, ... (5 entities in total)
• Functional Keywords: protein tyrosine kinase, dual specificity, splicing, human, inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40351.35

Authors

Schroeder, M.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Paruch, K.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2018-11-13, release date: 2019-01-16, Last modification date: 2024-01-24)

Primary citation

Nemec, V.,Hylsova, M.,Maier, L.,Flegel, J.,Sievers, S.,Ziegler, S.,Schroder, M.,Berger, B.T.,Chaikuad, A.,Valcikova, B.,Uldrijan, S.,Drapela, S.,Soucek, K.,Waldmann, H.,Knapp, S.,Paruch, K.
Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.
Angew. Chem. Int. Ed. Engl., 58:1062-1066, 2019

PubMed Abstract: Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.

PubMed: 30569600
DOI: 10.1002/anie.201810312

Experimental method

X-RAY DIFFRACTION (1.49 Å)