ELF programmes available for partnering

The aim of this programme was to identify novel inhibitors of the interaction of viral spike protein subunit S1 and human angiotensin-converting enzyme 2 (ACE2) as a small-molecule therapeutic option to protect against SARS-CoV2 infections and minimize disease severity in SARS-CoV2 patients. First-in-class small-molecule medications with novel mode-of-action can limit further spread of the disease in unvaccinated populations, but also minimize the risk of poor vaccine efficacy against new variants of SARS-CoV2. This Programme developed a very comprehensive screening assay cascade for hit triaging, resulting in high-quality hits comprising of various compound clusters and singletons. For the most promising 11-resynthesized compounds the inhibitory activity was validated.

The screening programme entailed the following:

The primary screen using Trimeric S1 - hACE2 interaction HTRF binding assay resulted in primary actives that were reconfirmed and a specific or technology interfering false positives were subsequently deselected through a counter-screen using an unrelated PPI HTRF assay. The confirmed actives were further triaged with a label-free MALDI-TOF assay tailored to measure the peptidase activity of human ACE2 in dose-response curve (DRC) analysis. Compounds that inhibited human ACE2 enzymatic activity were excluded to minimize the risk of on-target toxicities. Finally, DRC analysis was conducted on the remaining compounds using the primary assay to determine the pEC50, Emax, and hill slopes and Thermal Shift Assay (TSA) was done to confirm target engagement, laying the foundation of Preliminary Hit List (PHL) selection, followed by LC-MS analysis and the Revised Hit List (RHL). Finally, 48 compounds were selected for the Qualified Hit List (pEC50 4.75-5.98), of which 15 compounds were recommended for resynthesis and further validation. A total of 12 compounds were successfully resynthesized, of which the activity of 11 was reconfirmed.

This SARS-CoV-2 programme is now open for partnering for:

• Profiling hit series in cellular viral entry assays and efficacy determination for other spike variants
• Mode-of-action determination
• Structure-enabled computational chemistry
• Hit-to-lead chemistry and Structure-Activity Relationship (SAR) studies
• In-vitro ADME-Tox studies
• In-vivo Proof of Concept

Deletion of a specific periplasmic chaperone in Gram-negative pathogens such as Pseudomonas aeruginosa, Yersinia enterocolitica, uropathogenic Escherichia coli, Salmonella enterica and Shigella flexneri leads to reduced virulence as well as increase of antibiotic susceptibility. This Programme identified potential inhibitors. Out of ten most promising hits, two candidates were selected for further optimization. To this end, the Programme Owner tested the activity of available shelf derivatives, performed also in silico docking and MD simulations, and carried out further analyses beside the primary assay. The assays included Kd determination by MST, melting point analysis by nanoDSF, waterLOGSY NMR, cytotoxicity assays using eukaryotic cell lines and modified MIC assays using E. coli. The team is now looking for funding opportunities and or partners for further development of these leads.

This is an in vivo Proof of Concept, targeting an ion channel with the potential to generate a new class of analgesic drugs, with the opportunity to treat chronic pain without affecting normal sensation and perception. This project has identified a number of highly potent and selective ion channel enhancers using a combination of fluorescent Tl+ flux screening and electrophysiology assays. Kinetic analysis of these data sets has allowed for triaging of compounds by modality of action, selecting for the most pharmacological advantageous profiles. Exemplar compounds from the lead series have been further profiled, exploring their pharmacokinetic and ADME properties both in vitro and in vivo. By partnering, the project team hopes to further develop their in vivo testing for efficacy in pain conditions and continue toxicology and ADME testing.

This programme has been developed by Graeme Wilkinson’s team at The Research Network Ltd. In collaboration with the European Lead Factory, they have identified and further exemplified novel lead-like compounds that are potent, sub-nM inhibitors of the MrgD receptor. In addition, they have generated pharmacokinetic data, which supports their oral bioavailability. Their goal is to build on this work and identify candidate molecules that have the potential for clinical development in pain and / or itch (pruritus). This will be done through a focused lead optimisation campaign that will include the demonstration of efficacy and target engagement.

We have a programme developed in Italy that is applicable for a range of human diseases, with highly variable phenotypes, affecting the skeletal system (e.g. brachyolmia type 3 & spondyloepiphyseal dysplasia), and the peripheral nervous system (e.g. Charcot-Marie-Tooth disease type 2). The scope of the project is the development of selective TRPV4 antagonists. After HTS on a recombinant human TRPV4 cell-based assay, 50 molecules showing pIC50 > 5 on TRPV4 and pIC50 < 4.7 on mock cells were prioritised. Some Hits appear to possess interesting levels of potency, with a pIC50 > 7. The team is looking for a partner with complementary expertise and capabilities in medicinal chemistry, in vitro ADME, in vivo PK, and animal models to further develop the molecules through the subsequent phases of drug discovery.

Trypanosomatid parasites cause a variety of devastating neglected diseases in humans and their livestock, including leishmaniasis, Chagas disease and animal African trypanosomiasis. A characteristic property of these organisms is a remarkably complex mitochondrial RNA editing process that, as a key player, involves an enzyme called RNA editing ligase 1 (REL1). An ELF programme has targeted REL1 and delivered chemically diverse small molecule inhibitors, some of which inhibit REL1 from several trypanosomatid species. The Programme Owner’s laboratory has expertise in molecular parasitology, biophysical characterisation of protein-ligand interactions and protein crystallography and has access to animal models of disease. They are now looking for partners with complementary expertise in medicinal chemistry and ADME/PK to further develop the molecules through the subsequent phases of drug discovery.

Adrenomedullin receptor (AM) antagonists as potential therapeutic targets for major depressive disorder. This program has identified non-peptidic modulators of the AM receptor called AM2. These compounds could be a crucial first step towards the elucidation the biological function/activity of this receptor, with a view to develop novel therapies for the treatment conditions such as MDD, anxiety disorders and chronic pain.

AM is a 52 amino acid peptide hormone that has partial structural homology with the calcitonin gene-related peptide (CGRP). It has shown anti-inflammatory activities and has previously been linked with several psychiatric disorders, as well as chronic pain. AM has been proposed to have several functions in the CNS including neurogenesis. AM works through a complex of three proteins including the G protein-coupled receptor related to the calcitonin receptor, CALCRL, and the CGRP-receptor component protein, RCP. CALCRL and RCP associate with two different receptor activity-modifying proteins (RAMPs) generating two different AM receptors (CALCRL+RAMP2 = AM1 and CALCRL+RAMP3 = AM2), which are essential for functional activity. This program focused on the discovery of AM2 antagonists.

Chronic pain effects 18% of people and comes at a substantial personal and economic cost. NICE guidelines authorise the use of a range of analgesics including non-steroidal anti-inflammatory agents and opioids. This project aims to identify selective ssGlyR α3 agonists to restore inhibitory tone and dampen excitatory transmission. 31 structural clusters were identified of which 25 are singleton clusters. This hit list is available for partnering and further development.

X-linked Inhibitor of Apoptosis Protein (XIAP) is a key blocker of apoptosis and is linked with promoting cancer cell survival. A significant amount of interest in this and other Inhibitor of Apoptosis Proteins (IAPs) has led to the development of a range of non-selective XIAP/IAP inhibitors, although the non-selective targeting of IAPs results in TNF-α release, potentially limiting the clinical efficacy of these types of molecule. This hit list resulting from this programme, which lists 36 compounds, is available for partnering to be further developed.

The programme proposes to identify small molecule modulators of the PD-1::PD-L1 interaction as potential therapeutics for the treatment of cancer. The target has been validated with marketed successful mAb therapeutics and identified as an important mechanism for cancer cells to evade an immune response. Small molecule druggability is indicated by recently released patents which indicate that highly potent molecules can be identified. Ten structural clusters were identified of which five singleton clusters. These compounds were resynthesized and retested in established assays. This improved hit list is available for partnering to be further developed.

ULK1 is a key enzyme in autophagy, the process whereby cells catabolise intracellular components enabling them to survive starvation and stress. Cancer cells are believed to use autophagy to survive stress conditions inside a tumour and to protect against the effects of radiotherapy. Inhibition of autophagy has also been shown to reduce cell motility in metastatic cell lines. The programme was set out to to discover and develop inhibitors of ULK1 to explore its potential as a clinical target and to develop potent compounds without the selectivity or metabolic liabilities that are exhibited by current small molecules. It has resulted in a hit list and a cluster of newly designed, synthesised and tested compounds, which are now available for partnering.

Scientists from the Yarwood Lab and the European Screening Centre have jointly published on the discovery of a new class of EPAC activators. The study, which describes the identification, optimisation and characterisation of a new chemical class of selective agonists for EPAC1, is the result of another successful collaboration within the framework of the European Lead Factory (ELF).

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Scientists from the German Cancer Research Center (DKFZ) have successfully discovered potent and selective inhibitors of enzymes associated with the development of some cancers and neurodegenerative diseases. Published in ChemMedChem, the findings mark a significant step in the development of potential new cancer treatments.

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Keapstone Therapeutics is preparing to make the next steps in clinical candidate selection and first-in-human studies. This investment brings the total seed investment to € 2,4 million. Last year Parkinson’s UK together with Sheffield University launched the virtual biotech Keapstone Therapeutics to further develop compounds that boost the internal cellular defence mechanisms against oxidative stress to combat neurodegenerative diseases.

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Servier, an independent international pharmaceutical company, and Scandicure, a Swedish spin-out of the University of Gothenburg, today announced the establishment of an agreement to exploit Scandicure’s innovation in the field of metabolic disease. Scandicure, in collaboration with the IMI-funded European Lead Factory, has developed inhibitors of a novel biological target for non-alcoholic steatohepatitis (NASH), type-2 diabetes and potentially other metabolic diseases.

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Metabomed, an Israeli biotech company that has been successful in progressing results through the European Lead Factory (ELF), has discovered a series of potent and selective inhibitors of ACSS2 (the AcetylCoA Short chain Synthase 2 enzyme) for the treatment of cancers dependent on acetate metabolism. Metabomed’s recent successes have led to the company securing a further $12.5 million in funding. These funds will go towards moving the clinical candidate for its ACSS2 programme towards IND approval.

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In his screening proposal to ELF, Professor van der Stelt suggested to search for new inhibitors of NAPE-PLD, the protein responsible for the production of anandamide in the brain. The ELF partners carried out High-Throughput Screening (HTS) on the JECL and performed deselection assays ending up with five high-quality hits with four different chemotypes. Further optimisation of the hits by the Leiden chemists and their collaborators led to the discovery and characterisation of LEI-401 as the first CNS-active NAPE-PLD inhibitor. The findings presented by the team may open up new avenues for the treatment of anxiety disorders like post-traumatic stress.

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The University of Oxford takes the next step in targeting antimicrobial resistance, with help of the results and hit compounds delivered by the European Lead Factory. The Oxford team, led by Professor Chris Schofield, has got the opportunity to collaborate with the European Gram-Negative Antibacterial Engine (ENABLE) project to further progress this programme towards clinical development.

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Leishmania parasites cause leishmaniasis, a neglected tropical disease found in parts of tropics, subtropics and Southern Europe. The infection is transmitted through the bite of infected phlebotomine sand flies. Among the several forms of leishmaniasis, visceral leishmaniasis is the most severe form of the disease, which is fatal when left untreated. At the moment, there is no approved human vaccine and disease control relies mostly on chemotherapy, which is frequently linked to safety issues, drug resistance, among other issues, hindering disease eradication in endemic areas. Coming up with new chemotherapeutic options is, therefore, of utmost importance.

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With help of the European Lead Factory, the Phosphodiesterase Inhibitors for Neglected Parasitic Diseases (PDE4NPD) project takes the next step towards developing novel drugs against kinetoplastid parasites such as Trypanosoma brucei, the causative parasite of African sleeping sickness, and Trypanosoma cruzi, causing Chagas disease.

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The Netherlands Translational Research Center (NTRC) has identified IDO1 inhibitors with best-in-class properties. They have been developed from a series of inhibitor compounds first identified by screening the JECL of the European Lead Factory against IOD1 and TDO, important targets in cancer immunotherapy. IDO1 and TDO are two structurally unrelated proteins that both catalyse the degradation of the amino acid tryptophan and regulate the T cell response. Thus, inhibition of IDO1 or TDO restore the body’s immune response against cancer cells. IDO1 and TDO inhibitors may also increase the efficacy of immunotherapy with immune checkpoint inhibitors.

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Complementing the current anti-leukaemia arsenal with an inhibitor of this protein would have an impact in terms of survival, but also specifically in relapse prevention by suppressing leukemic residual disease. This target is a kinase with a pivotal role in the cytoskeleton dynamics. The cytoskeleton is involved in the cell division and proliferation of cancer. Screening this target against the compounds in the Joint European Compound Library during the Qualified Hit List (QHL) phase lead to finding chemical matter that was clearly different from what they had found before.

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