6P0P

Human beta-tryptase co-crystal structure with 5-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-2-(3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}-[1,1'-biphenyl]-3-yl)-2-hydroxy-2H-1,3,2-benzodioxaborol-2-uide

6P0P の概要

• エントリーDOI: 10.2210/pdb6p0p/pdb
• 分子名称: Tryptase alpha/beta-1, (3'-{4-[3-(aminomethyl)phenyl]piperidine-1-carbonyl}[1,1'-biphenyl]-3-yl){4-[3-(aminomethyl)phenyl]piperidin-1-yl}[3,4-di(hydroxy-kappaO)phenyl]methanonato(2-)hydroxyborate(1-), SULFATE ION, ... (6 entities in total)
• 機能のキーワード: tryptase, bivalent inhibitor, protease inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62633.68

構造登録者

Giardina, S.F.,Pingle, M.R.,Werner, D.S.,Feinberg, P.B.,Foreman, K.W.,Bergstrom, D.E.,Arnold, L.D.,Barany, F. (登録日: 2019-05-17, 公開日: 2020-03-25, 最終更新日: 2024-10-30)

主引用文献

Giardina, S.F.,Werner, D.S.,Pingle, M.,Feinberg, P.B.,Foreman, K.W.,Bergstrom, D.E.,Arnold, L.D.,Barany, F.
Novel, Self-Assembling Dimeric Inhibitors of Human beta Tryptase.
J.Med.Chem., 63:3004-3027, 2020

PubMed Abstract: β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.

PubMed: 32057241
DOI: 10.1021/acs.jmedchem.9b01689

実験手法

X-RAY DIFFRACTION (2.55 Å)