Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

Liang, Guyan; Aldous, Suzanne C.; Merriman, Gregory; Levell, Julian; Pribish, James; Cairns, Jennifer; Chen, Xin; Maignan, S.; Mathieu, Magali; Tsay, Joseph; Sides, Keith; Rebello, Sam; Whitely, Brian; Morize, Isabelle; Pauls, Henry W.

doi:10.1016/j.bmcl.2011.11.119

Cited by 22 publications

(16 citation statements)

References 31 publications

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“…Based on unit cell volume and proposed protein content, a single bI-tryptase,Fab,STI complex was expected in the crystallographic asymmetric unit. The structure was solved using molecular replacement (McCoy et al, 2007) in space group P6 2 22 using as search probes a previously determined tryptase protomer derived from PDB accession 4A6L (Liang et al, 2012) STI from PDB 1AVU (Song and Suh, 1998), an Fv fragment stripped of CDR loops from PDB 1FVC (Eigenbrot et al, 1993), and the constant region from PDB 1FVD, each as separate bodies.…”

Section: Crystallization and Structural Determinationmentioning

confidence: 99%

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Maun

Jackman

Choy

et al. 2019

Cell

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Section: Crystallization and Structural Determinationmentioning

confidence: 99%

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Maun

Jackman

Choy

et al. 2019

Cell

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“…Additionally, the N1-acyl moieties are positioned proximally to adjacent catalytic subunits, providing a convenient location for bridging between monomers. 24,34 Based on the co-crystal structure of tryptase bound to a 3APA analogue, 33 we designed a series of lowpotency compounds that could reversibly combine to form more potent, functional dimers.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Bivalent inhibitors that engage two adjacent primary specificity pockets (S1 pockets) of the tryptase homotetramer have demonstrated remarkable increases in selectivity and affinity. 24,25 However, these molecules have poor druglike performance and precluded good bioavailability, 24−28 partly due to their large size. Clinical trials with earlier agents, together with recent animal studies, have established that tryptase is an excellent target for a variety of inflammatory indications, and the promise of more potent and selective inhibition makes it an attractive target for drug development.…”

Section: ■ Introductionmentioning

confidence: 99%

Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase

Giardina

Werner²,

Pingle

et al. 2020

J. Med. Chem.

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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.

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“…Here, we speculate that MCDPT and MCAPT together could be putative tissue biomarkers of pancreatic cancer angiogenesis status. To this regard, tryptase targeting through tryptase inhibitors, such as gabexate or nafamostat mesylate, could become an interesting strategy as a novel antiangiogenetic intervention in pancreatic cancer patients [ 86 , 87 , 88 , 89 , 90 ]. On the other hand, MC degranulation could be inhibited by c-KitR tyrosine kinase inhibitors, such as masitinib, as first applied in veterinary clinical oncology and then translated to humans for the treatment of PDAT patients, with interesting results, as reported by the only phase 3 clinical trial [ 91 , 92 , 93 , 94 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Mast Cells Positive for c-Kit Receptor and Tryptase Correlate with Angiogenesis in Cancerous and Adjacent Normal Pancreatic Tissue

Ammendola

Currò

Laface

et al. 2021

Cells

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Background: Mast cells (MCs) contain proangiogenic factors, in particular tryptase, associated with increased angiogenesis in several tumours. With special reference to pancreatic cancer, few data have been published on the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue (PDAT) and adjacent normal tissue (ANT). In this study, density of mast cells positive for c-Kit receptor (MCDP-c-KitR), density of mast cells positive for tryptase (MCDPT), area of mast cells positive for tryptase (MCAPT), and angiogenesis in terms of microvascular density (MVD) and endothelial area (EA) were evaluated in a total of 45 PDAT patients with stage T2–3N0–1M0. Results: For each analysed tissue parameter, the mean ± standard deviation was evaluated in both PDAT and ANT and differences were evaluated by Student’s t-test (p ranged from 0.001 to 0.005). Each analysed tissue parameter was then correlated to each other one by Pearson t-test analysis (p ranged from 0.01 to 0.03). No other correlation among MCDP-c-KitR, MCDPT, MCAPT, MVD, EA and the main clinical–pathological characteristics was found. Conclusions: Our results suggest that tissue parameters increased from ANT to PDAT and that mast cells are strongly associated with angiogenesis in PDAT. On this basis, the inhibition of MCs through tyrosine kinase inhibitors, such as masitinib, or inhibition of tryptase by gabexate mesylate may become potential novel antiangiogenetic approaches in pancreatic cancer therapy.

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Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

Cited by 22 publications

References 31 publications

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

An Allosteric Anti-tryptase Antibody for the Treatment of Mast Cell-Mediated Severe Asthma

Novel, Self-Assembling Dimeric Inhibitors of Human β Tryptase

Mast Cells Positive for c-Kit Receptor and Tryptase Correlate with Angiogenesis in Cancerous and Adjacent Normal Pancreatic Tissue

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