5U9D

Discovery of a potent BTK inhibitor with a novel binding mode using parallel selections with a DNA-encoded chemical library

Summary for 5U9D

• Entry DOI: 10.2210/pdb5u9d/pdb
• Descriptor: Tyrosine-protein kinase BTK, (R)-N-methyl-2-(3-((quinoxalin-6-ylamino)methyl)furan-2-carbonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: brutons tyrosine kinase, btk, protein kinase, dna encoded library, proteros biostructures gmbh, antitumor protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 1
• Total formula weight: 32477.25

Authors

Cuozzo, J.W.,Centrella, P.A.,Gikunju, D.,Habeshian, S.,Hupp, C.D.,Keefe, A.D.,Sigel, E.,Soutter, H.H.,Thomson, H.A.,Zhang, Y.,Clark, M.A. (deposition date: 2016-12-16, release date: 2017-01-18, Last modification date: 2024-03-06)

Primary citation

Cuozzo, J.W.,Centrella, P.A.,Gikunju, D.,Habeshian, S.,Hupp, C.D.,Keefe, A.D.,Sigel, E.A.,Soutter, H.H.,Thomson, H.A.,Zhang, Y.,Clark, M.A.
Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNA-Encoded Chemical Library.
Chembiochem, 18:864-871, 2017

PubMed Abstract: We have identified and characterized novel potent inhibitors of Bruton's tyrosine kinase (BTK) from a single DNA-encoded library of over 110 million compounds by using multiple parallel selection conditions, including variation in target concentration and addition of known binders to provide competition information. Distinct binding profiles were observed by comparing enrichments of library building block combinations under these conditions; one enriched only at high concentrations of BTK and was competitive with ATP, and another enriched at both high and low concentrations of BTK and was not competitive with ATP. A compound representing the latter profile showed low nanomolar potency in biochemical and cellular BTK assays. Results from kinetic mechanism of action studies were consistent with the selection profiles. Analysis of the co-crystal structure of the most potent compound demonstrated a novel binding mode that revealed a new pocket in BTK. Our results demonstrate that profile-based selection strategies using DNA-encoded libraries form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets.

PubMed: 28056160
DOI: 10.1002/cbic.201600573

Experimental method

X-RAY DIFFRACTION (1.33 Å)