Science Pool

Blood microsampling is a less invasive and simplified alternative to traditional venipuncture for PK/TK sampling, used mainly in small-animal studies. The purpose of this work was to evaluate the possibility of using microsampling technique also to support PK/TK studies in non-human primates.
A comparison of plasma PK parameters was conducted by traditional blood collection from the femoral vein and microsampling from the tail vein of six non-naïve cynomolgus monkeys. Four drugs were selected for this comparison, based on acid-base properties and volume of distribution. 
The results obtained in this work, supported by robust statistics, demonstrated the suitability of microsampling in supporting PK/TK studies in non-human primates. 
The plasma exposures of the tested drugs are comparable for both sampling techniques and are not influenced by acid-base characteristics and volume of distribution. 
Microsampling used in non-human primates avoids the occurrence of hematomas at the animal sampling site and can also refine practices to limit pain and distress to which animals are exposed (refinement of 3Rs) and, as a result, may reduce the impact of animal stress on PK/TK readouts; moreover, it also provides significant advantages for animal technicians during in life handling.

To request a copy of the article, contact the authors. For Evotec: massimo.breda@evotec.com

In this collaborative paper, recently published in J. Med. Chem., 10.1021/acs.jmedchem.2c02087, Chiesi Farmaceutici and Evotec  describe the efforts to identify a potent and selective, orally bioavailable,  Lysophosphatidic Acid Type 2 (LPA2) Receptor Antagonists to treat Idiopathic pulmonary fibrosis (IPF) or other fibrotic disorders. 

The article is an example of how early Dose to Man (eD2M) prediction can be efficiently used to guide Hit to Lead and Lead Optimization when potency and metabolic stability are the main parameters to be optimized. eD2M exploits only in vitro parameters (activity in the primary assay and metabolic stability in human microsomes) and it was extremely useful to monitor project progression and to prioritize compounds for in vivo PK studies. Starting from an LPA2 antagonist compound reported in the literature and following our multiparametric optimization strategy, we were able to identify compound 58, showing a 45000-fold eD2M improvement compared to the starting hit. Additionally, compound 58 exhibits excellent potency, selectivity, and oral in vivo PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

IPF is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of the functionality of the lungs. The drugs currently available to patients can slow down the progression of the disease, but there are no treatments that can prevent or block it.

To request a copy of the article, contact the authors. For Evotec: luca.raveglia@evotec.com

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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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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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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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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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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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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The 13^th 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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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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