Science Pool

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

READ NOW

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.

DOWNLOAD

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

LEARN MORE

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.

READ NOW

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

LEARN MORE

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.

DOWNLOAD

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.

DOWNLOAD

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.

DOWNLOAD

LEARN MORE

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.

LEARN MORE