5U9D

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

5U9D の概要

• エントリーDOI: 10.2210/pdb5u9d/pdb
• 分子名称: 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)
• 機能のキーワード: brutons tyrosine kinase, btk, protein kinase, dna encoded library, proteros biostructures gmbh, antitumor protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q06187
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32477.25

構造登録者

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. (登録日: 2016-12-16, 公開日: 2017-01-18, 最終更新日: 2024-03-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.33 Å)