Science Pool

Filling a nick in NIK

Posted by Evotec on Jun 21, 2023 1:51:59 PM

Inhibition of NF-κB inducing kinase (NIK) has been pursued as a promising therapeutic target for autoimmune disorders due to its highly regulated role in key steps of the NF-κB signaling pathway. Previously reported NIK inhibitors from our group were shown to be potent, selective, and efficacious, but had higher human dose projections than desirable for immunology indications. Herein we report the clearance-driven optimization of a NIK inhibitor guided by metabolite identification studies and structure-based drug design. This led to the identification of an azabicyclo[3.1.0] hexanone motif that attenuated in vitro and in vivo clearance while maintaining NIK potency and increasing selectivity over other kinases, resulting in a greater than ten-fold reduction in predicted human dose.

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Tags: Medicinal Chemistry, Articles & Whitepapers, ADME/DMPK, In vitro Biology, Immunology & Inflammation

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1

Posted by Evotec on Mar 7, 2023 12:05:56 PM

Originally presented in Science Translational Medicine, this article co-written with Merck & Co. presents a set of bifunctional HIV therapies, dubbed targeted activator of cell kill (TACK) molecules, that were optimized for simultaneous antiviral activity and selective elimination of infected CD4+ T cells from HIV-1 patients.

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Tags: Articles & Whitepapers, Structural Biology & Protein Science, Immunology & Inflammation

Natural and synthetic 2-oxoglutarate derivatives are substrates for oncogenic variants of human isocitrate dehydrogenase 1 and 2

Posted by Evotec on Mar 7, 2023 11:55:59 AM

Variants of isocitrate dehydrogenase IDH 1 and 2 are known to alter the metabolism in cancer cells. Through a combined approach of X-ray crystallography and 1H NMR in collaboration with Christopher Schofield from University of Oxford, we reveal that 2OG derivatives can serve as substrates of the investigated IDH1/2 variants, but not of WT IDH1/2, and have the potential to act as 2OG-competitive inhibitors.

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Tags: Oncology, Articles & Whitepapers, Structural Biology & Protein Science

Quality Assurance-Based Key Performance Indicators

Posted by Evotec on Mar 1, 2023 1:33:19 PM

In November 2022, our Quality Assurance expert Michelle Manton presented the topic of Quality Assurance-Based Key Performance Indicators (KPIs) at the RQA International QA Conference in Brighton, alongside other members of the GLP Committee.

This article captures the discussions and feedback received during that workshop with the intention of promoting reflection on how experts in the quality profession use KPIs, what they aim to achieve and how they can use KPIs or similar metrics to drive continuous improvement – the heart of any robust ‘future-proofed’ Quality Management System (QMS).

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Tags: Articles & Whitepapers, Blog

The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile

Posted by Evotec on Dec 2, 2022 10:31:14 AM

The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent

This publication details the discovery of a series of selective agonists for Transient Receptor Potential Melastatin 5 (TRPM5) culminating with the identification of a lead compound.

Gastrointestinal (GI) disease including inflammatory bowel disease (ulcerative colitis and Crohn’s disease), and GI motility disorders (neuropathic constipation (NC), and gastroparesis) are serious life limiting conditions for patients. TRPM5 is a non-selective monovalent cation channel activated by intracellular Ca2+ increase which, within the GI system, plays a critical role of propagating the signal through membrane depolarization and initiating the release of Interleukin (IL)-25 and other paracrine factors. We hypothesized that a TRPM5 agonist will activate the release of IL-25 and non-neuronal ACh, leading to improvement in motility through a prokinetic mechanism.

In the paper we describe: 

  • The process of our discovery starting from a high throughput screening hit through to the identification of a lead compound
  • The selectivity of the lead compound versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8
  • The drug metabolism and pharmacokinetics (DMPK) profile of the lead compound
  • The in vivo efficacy of lead compound in a mouse model of gastrointestinal motility

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Tags: Articles & Whitepapers, In vitro Biology, Metabolic Disease & Complications

Rare Diseases DDxp

Posted by Evotec on Nov 17, 2022 5:12:36 PM

Volume 1 of Evotec's DDxp (Drug Discovery Expertise) series focuses on Rare Diseases, looking particularly at Gene Therapy and Huntington's Disease. The articles are written by our in house experts and also feature Sarah Winckless, an Olympic and World Champion rowing medallist, who documents her own experience with Huntington's Disease.

Download it now to find out more.

 

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Tags: Articles & Whitepapers, Rare Diseases

PanHunter Multi-Omics Data Analysis DDup #13

Posted by Evotec on Nov 3, 2022 10:31:09 AM

The 13th edition of our Drug Discovery Update (DDup) provides insights into our unique PanHunter next generation multi-omics data analysis platform.

In this edition, it covers:

  • an introduction to PanHunter and multi-omics data analysis including:
    • the importance of multi-omics data (genomics, transcriptomics, proteomics and metabolomics) in understanding the complexity of disease and treatments
    • how the versatile and interactive multi-omics analysis platform, PanHunter, can greatly simplify the data analysis and interpretation process and so reduce time, improve visualisation and contextualisation, and inform decisions
    • how PanHunter can access additional meta information, reference data, chemical and structural information and clinical data to  provide further relevance and perspective
  • an interview with Dr John Szilagyi at Bristol Myers Squibb on how he uses PanHunter and the benefits it brings
  • a case study on how PanHunter has been applied in rapid candidate biomarker discovery
  • user perspectives from different functions within Evotec (wet lab biologists, computational biologists and bioinformaticians) on how PanHunter is making an impact on their research

 

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Tags: Articles & Whitepapers, Proteomics, Metabolomics & Biomarkers, Modelling and Simulation

“Upcycling” known molecules and targets for drug-resistant TB

Posted by Evotec on Oct 27, 2022 9:57:18 AM

Despite recent reinvigorated efforts in Tuberculosis (TB) drug discovery, relatively few new drugs and candidates have emerged with clear utility against drug resistant TB. However, significant technological advances and learnings around target value have taken place offering opportunities to re-assess the potential for optimization of previously discovered chemical matter against Mycobacterium tuberculosis. A re-assessment of discarded compounds and programs from the “golden age of antibiotics” has yielded new scaffolds and targets against TB and uncovered classes with previously unappreciated utility for TB.

In this recent review, written by Evotec TB experts, Christine Roubert, Evelyne Fontaine and Anna Upton, these new perspectives, and the progress of these approaches are summarized, together with evident advantages and limitations of these strategies.

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Tags: Articles & Whitepapers

Transcriptomics Brings New Era of Toxicology Prediction

Posted by Evotec on Jul 22, 2022 11:57:59 AM

Featured in Nature, this article interviews experts, Paul Walker, Rüdiger Fritsch, and Carla Tameling, and provides the latest insights into transcriptomics and how the technology is transforming toxicology prediction.

It includes:

  • an overview of the current challenges in predicting organ-specific toxicity especially DILI
  • the advantages of using human cell-based models with a particular focus on 3D organoid models
  • a background to transcriptomics and how advances in throughput have widened its application 
  • how combining transcriptomics with machine learning and artificial intelligence has increased the power of this technology in toxicology prediction

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Tags: Articles & Whitepapers, Toxicology & Safety, Modelling and Simulation

Combined treatment with a selective PDE10A inhibitor TAK-063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic-like effects

Posted by Evotec on Jun 27, 2022 4:06:02 PM

Novel phosphodiesterase 10A inhibitor drugs, through a distinct mechanism on striatal dopamine receptors, could raise the possibility of producing an augmented pharmacological antipsychotic effects by a combination therapy with the standard antipsychotic drug.

TAK-063 is a novel phosphodiesterase 10A inhibitor which has been evaluated for this hypothesis. Results show that the use of TAK-063 can produce augmented antipsychotic-like activities in combination with antipsychotics without alteration of plasma prolactin levels and catalepsy

In this collaborative paper with Takeda, we demonstrate that:

  • Combined treatment with TAK-063 and either haloperidol or olanzapine leads to a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum.
  • TAK-063 enhances N-methyl-D-aspartic acid receptor mediated synaptic responses in rat cortical striatal slices in both direct and indirect pathway MSNs to a similar extent.
  • Co-administration of TAK-063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway.
  • Combined treatment with TAK-063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine- or MK-801-induced hyperactivity in rats and MK-801-induced deficits in prepulse inhibition in mice.
  • TAK-063 did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats.

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Tags: Neuroscience, Articles & Whitepapers, Hit & Target ID/Validation, In vitro Biology