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

Summary for 6P0P

• Entry DOI: 10.2210/pdb6p0p/pdb
• Descriptor: 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)
• Functional Keywords: tryptase, bivalent inhibitor, protease inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 62633.68

Authors

Giardina, S.F.,Pingle, M.R.,Werner, D.S.,Feinberg, P.B.,Foreman, K.W.,Bergstrom, D.E.,Arnold, L.D.,Barany, F. (deposition date: 2019-05-17, release date: 2020-03-25, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.55 Å)