Science Pool

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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Learn more about fighting tuberculosis by targeting the essential enzyme PptT.

Together with collaborators at Weill Cornell Medical College, Texas Agricultural and Mechanical University (TAMU), and  University of North Carolina (UNC), we identified the amidinourea compound AU8918, through a phenotypic screen, as an interesting anti-TB compound. We went on to identify its target within Mycobacterium tuberculosis, as phosphopantetheinyl transferase (PptT) - an essential enzyme involved in synthesis of cellular lipids and virulence factors.

This paper describes:

• Next steps taken in further pursuit of this novel anti-TB series
• An expanded collaboration within the TB Drug Accelerator consortium
• Latest structure guided SAR exploration around AU8918 for more potent and safest Lead-like analogs

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SARM1 is a NADase whose action triggers the destruction of axons and development of novel SARM1 inhibitors which enables the prevention or delay of neurodegenerative disorders. This paper identifies the binding site for the SARM1 agonist NMN and reveals the structure of full-length SARM1 as elucidated by cryo-electron microscopy (cryo-EM). The structure of apo SARM1 was revealed as an octameric ring, held in an autoinhibitory state by the separation of the active TIR domain at the rim of the ring. The elucidation of autoinhibition release and the identification of the NMN binding site within the autoinhibitory ARM domain opens a path to inhibition of SARM1 via stabilisation of its inactive form. These studies were possible through the close co-ordination of the new cryo-EM team at Evotec, Abingdon with Disarm and academic collaborators in Australia and the USA.

Proposed SARM1 activation mechanism:

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