European Lead Factory

Giordanetto, Fabrizio; Jones, Philip S.; Nelson, Adam; Benningshof, Jorg C. J.; Müller, Gerhard; Pannifer, Andrew; Boeckel, Stan van; Tzalis, Dimitrios

doi:10.1016/b978-0-12-409547-2.12303-0

Cited by 3 publications

(2 citation statements)

References 45 publications

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“…While success rates in discovery and development of new medicines remain low and unmet medical needs are still a huge burden on global health care, 1 , 2 many academic discoveries with great potential for pharmaceutical exploitation have remained underutilized. 3 , 4 The underlying reason for this is that, on one hand, academic labs typically lack the resources, infrastructure, and expertise to progress early-stage biomedical discoveries toward development and, on the other hand, pharmaceutical companies and venture capitals are mainly attracted to investing in the later-stage de-risked projects.…”

Section: Introductionmentioning

confidence: 99%

Hit Discovery for Public Target Programs in the European Lead Factory: Experiences and Output from Assay Development and Ultra-High-Throughput Screening

Honarnejad¹,

Boeckel²,

Hurk³

et al. 2021

SLAS Discovery

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Section: Introductionmentioning

confidence: 99%

Hit Discovery for Public Target Programs in the European Lead Factory: Experiences and Output from Assay Development and Ultra-High-Throughput Screening

Honarnejad¹,

Boeckel²,

Hurk³

et al. 2021

SLAS Discovery

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“…High-throughput screening and validation of a promising hit Using our previously published KLK6 assay format, [21] we performed a HTS with the European Lead Factory (ELF), [22] and tested ~350,000 substances at 10 M for their ability to reduce KLK6-catalyzed hydrolysis of the fluorogenic Boc-Phe-Ser-Arg-AMC peptide. About 8,000 actives were identified and re-tested.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6

Vita¹,

Smits²,

Hurk³

et al. 2019

Preprint

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Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 and 34 have single digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivity, respectively, against the closely related enzyme trypsin. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

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Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

Vita

Smits²,

Hurk³

et al. 2019

ChemMedChem

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Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high‐throughput screen within the European Lead Factory program. Structure‐guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6‐dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

show abstract

European Lead Factory

Cited by 3 publications

References 45 publications

Hit Discovery for Public Target Programs in the European Lead Factory: Experiences and Output from Assay Development and Ultra-High-Throughput Screening

Hit Discovery for Public Target Programs in the European Lead Factory: Experiences and Output from Assay Development and Ultra-High-Throughput Screening

Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6

Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

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