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

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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Originally published in Chemistry Europe.

A stereocontrolled and modular total synthesis of Lipoxin B4 (LXB4) was developed in 25% overall yield in just 10 steps. Previously reported syntheses to date were generally low yielding, together with long synthetic routes and lack full spectral characterization for LXB4. Download the article to learn more.

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In this work, published in collaboration with Boston Children's Hospital, Evotec actively contributed to the identification of DW0254 and small molecule analogs capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. Photoaffinity labelling mass spectrometry (PALMS) approach was successfully applied to identify PDE6D as the molecular target of DW0254. PALMS and biophysical methods were also used to identify the binding site of DW0254 in PDE6D. Our study provides evidence that PDE6D-dependent RAS trafficking with downstream activation of PI3K/AKT and RAC constitutes a novel potential therapeutic target in high risk leukemias.

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The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and there is great interest in developing SARM1 enzyme inhibitors as candidate therapies for multiple neurodegenerative diseases.

Through a combined approach of X-ray crystallography and cryo-EM we uncovered the molecular mechanism of SARM1 inhibition by a compound (DSRM-3716), demonstrating that it undergoes a base-exchange reaction with the nicotinamide moiety of NAD+, and that the transferase product is the bona fide inhibitor. Further more we reveal the activated state of SARM1 for the first time.

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Download this whitepaper to learn more about our integrated approach to drug abuse liability assessment including:

• The impact of scheduling
• Animal behavioural studies
• Human abuse liability studies

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Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19.

Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories.

• In this paper we describe strategies used to prioritize thousands of β-lactams from multiple companies into a small test set for further characterization.
• In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor.
• One potent cephaloporin was active in Mtb-infected mice.

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The 12^th edition of our Drug Discovery Update (DDup) provides insights into exciting new developments in 3D cell models including microtissues, organoids and organ-on-a-chip technology.

In this edition, it covers:

• an introduction to 3D cellular models
  • the need for better models to improve translation from in vitro to in vivo
  • the relevance of 3D cellular models to kidney disease modelling and drug induced toxicity prediction
• an overview of Evotec's 3D in vitro platforms
  • glomerulus-on-a-chip to study kidney disease
  • kidney organoids to study polycystic kidney disease
  • organ microtissues to predict drug-induced toxicity
• interviews with experts Dr Christodoulos Xinaris, Dr Reiner Class, Dr Magali Ferro and Dr Stephanie Ryder

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Huntington´s Disease (HD) is a hereditary neurodegenerative disorder that is caused by a mutation in the huntingtin gene (mHTT) leading to deposition of pathologic protein aggregates in the brain.

This paper focuses on:

• Visualization of mHTT aggregate expression by positron emission tomography (PET) in rodent HD model
• Utility of the previously described novel PET imaging ligand CHDI-180 for detection of mHTT in rodent and post-mortem human HD brain
• Ability of CHDI-180 to serve as functional response indicator for mHTT lowering therapies

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