Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform

Pant, Shishir M.; Mukonoweshuro, Amanda; Desai, Bimbisar; Ramjee, Manoj K.; Selway, Christopher N.; Tarver, Gary J.; Wright, A. G.; Birchall, Kristian; Chapman, Timothy M.; Tervonen, Topi A.; Klefström, Juha

doi:10.1021/acs.jmedchem.7b01698

Cited by 33 publications

(22 citation statements)

References 36 publications

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“…Despite the advances of machine learning, chemical reactor and assay technology, as of today, there are few published examples of fully integrated, automated, AI-driven discovery platforms. One such example is the automated closed-loop multiparameter design of selective hepsin inhibitors 190 . In progressing from the known inhibitor 1 to designed compound 2 in automated DMTA cycles, the IC50 value against hepsin was improved from ∼1 μM to 33 nM, and the selectivity over urokinase-type plasminogen activator (uPA) was increased from 30-fold to 100-fold.…”

Section: Box 5 Reducing Cycle Times By Automationmentioning

confidence: 99%

Rethinking drug design in the artificial intelligence era

Schneider

Walters

Plowright

et al. 2019

Nat Rev Drug Discov

523

349

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Perspective │2 Artificial intelligence (AI) tools are increasingly being applied in drug discovery. Whilst some protagonists point to vast opportunities potentially offered by such tools, others remain skeptical, waiting for a clear impact to be shown in drug discovery projects. The truth is probably somewhere between these extremes, but it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' for small-molecule drug discovery with AI and approaches to address them.

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Section: Box 5 Reducing Cycle Times By Automationmentioning

confidence: 99%

Rethinking drug design in the artificial intelligence era

Schneider

Walters

Plowright

et al. 2019

Nat Rev Drug Discov

523

349

View full text Add to dashboard Cite

show abstract

“…To date, antibodies and protease inhibitor-derived protein fragments have been reported, which inhibit hepsin activity in cancer invasion assays and mouse cancer models [83,128,129]. Moreover, a number of small molecule hepsin inhibitors have been developed, as described in more details in recent reviews [130][131][132][133]. It is anticipated that these small molecule hepsin inhibitors will be further optimized to improve their potency, selectivity, and oral availability, leading to clinical testing for cancer or other indications in the near future.…”

Section: Hepsin In Cancermentioning

confidence: 99%

Hepsin: a multifunctional transmembrane serine protease in pathobiology

Wang

Sun

et al. 2020

The FEBS Journal

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Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

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“…Cyclofluidic completed a number of collaboration projects, which demonstrated the capability to deliver new SAR data in a very efficient manner although only a small number were able to be published. 12 The ongoing translation of interest into long-term collaborations remained a challenge and probably no different to many other companies starting out.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Closing the Loop: Developing an Integrated Design, Make, and Test Platform for Discovery

Parry¹

2019

ACS Med. Chem. Lett.

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The relatively slow cycle time within medicinal chemistry from synthesis to assay is constantly being challenged to help improve the efficiency of the discovery process. While both synthesis and assay have been automated to varying degrees, there has, until recently, been limited focus on the complete design, make, and test process. This Innovations article outlines the development of Cyclofluidic from inception through to the commercialization of a fully integrated closed loop design, synthesis, and screen platform.

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Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform

Cited by 33 publications

References 36 publications

Rethinking drug design in the artificial intelligence era

Rethinking drug design in the artificial intelligence era

Hepsin: a multifunctional transmembrane serine protease in pathobiology

Closing the Loop: Developing an Integrated Design, Make, and Test Platform for Discovery

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