About

Background

For several years, we have been modelling and designing synthetic retinoids in order to study their biological effects acting through retinoid signalling pathways and affecting cellular development.

Through BBSRC-funded research we took these studies further to design novel synthetic retinoids as potential neurodegenerative disease drugs. We synthesised a diverse library of new structures and examined their biological activities through screening in a range of bioassays. This highlighted that some compounds showed both genomic and non-genomic effects which led us to the discovery of novel “dual acting” compounds, i.e. which could be potential drugs for tackling neurodegenerative diseases.

One lead compound in particular, had especially high activity (CNS exposure) and became our lead drug and its ability to trigger neurite outgrowth as one characteristic driving our drug development programme for application in ALS. In parallel, we are examining the mechanism of action of this class of compounds and taking our lead through preclinical studies and into more complex, disease-relevant models.

Image Descriptions

  1. Adult mouse lumber spinal cord section immunostained for the retinoic acid synthesizing enzyme RALDH2 showing expression in motorneurons (green).
  2. SH-SY5Y neuroblastoma cell line labelled over 72 hours with DC324 fluorescent RAR ligand.
  3. SH-SY5Y neuroblastoma cell line labelled over 72 hours with DC324 fluorescent RAR ligand.
  4. SH-SY5Y neuroblastoma cell line labelled with LC3B (autophagy marker) together with DC360 fluorescent RAR ligand over 72 hours.
  5. Adult mouse lumber spinal cord section immunostained for the retinoic acid synthesizing enzyme RALDH2 showing expression in motorneurons (green) with bisbenzimide (blue) stained nuclei.
  6. Adult mouse lumber spinal cord section immunostained for the retinoic acid synthesizing enzyme RALDH2 showing expression in a single motorneuron with bisbenzimide stained nuclei.

Core Team

The core development team have been working together as part of a close scientific collaboration for a number of years.

The present team started working together more closely and upon a focussed RCUK funded project involving retinoid signalling from 2016 via a BBSRC FoF project which resulted in a number exciting scientific results and importantly, the identification of a lead drug candidate for ALS in 2018.

This compound has continued to show excellent PK/ADME data since then and therefore, we setup a joint Durham and Aberdeen University spin-out company to license the relevant patent into, and to act a commercial development vehicle by which to drive the drug development programme forwards and raise the necessary investment required for the next stages.

Prof Andy Whiting
& Dr Ehmke Pohl
Durham University, Chemistry Department

Combining expertise in molecular modelling, docking and design, synthetic and medicinal chemistry making fluorescent analogues of the lead candidate and photoaffinity-enabled analogues, structural and biomolecular biology, RAR-drug binding.

Prof Peter McCaffery
& Dr Iain Greig
Aberdeen University, Medical Sciences

Vitro cellular biology and cell-based models, examining localisation, mode of action and target identification, PK/ADMET properties and planning toxicity and clinical trials.

Dr Alex Easton
& Dr Paul Chazot
Durham University, Psychology

Vivo animal studies in both wild-type and ALS/FTD animal models (principally mice), uniquely combining biological and behavioural effects, and pathological effects of drug versus disease in range of tissues as well as key neural (frontal and neuronal) tissues.

Key Partners
RAR-M Therapeutics uses Definition IP (UK) as IP advisors and has worldwide, exclusive licenses to the previous research in this field, and has patents to cover all existing species and applications.
Further to this RAR-M Therapeutics has taken a strategic approach to further extend its IP portfolio to cover new compounds, applications and therapeutic targets.

Key Papers

A Bioluminescence Reporter Assay for Retinoic Acid Controlof Translation of the GluR1 Subunit of the AMPA Glutamate Receptor

T. Khatib, B. Müller, A. Whiting, D. Chisholm, C. Redfern and P. McCaffery, Mol. Neurobiol., 2019,

DOI: 10.1007/s12035-019-1571-9

Genomic and non-genomic pathways areboth crucial for peak induction of neuriteoutgrowth by retinoids

T. Khatib, P. Marini, S. Nunna, D. R. Chisholm, A. Whiting, C. Redfern, I. Greig and P. McCaffery, Cell Commun. Signal., 2019,

DOI: 10.1186/s12964-019-0352-4

Novel Fluorescence Competition Assay for Retinoic Acid BindingProteins

C. Tomlinson, D. R. Chisholm, R. Valentine, A. Whiting and E. Pohl, ACS Med. Chem. Lett., 2018, 9, 1297-1300

Investment Opportunities

We are currently seeking supportive partners and investors for the development journey ahead, to complete preclinical work (est. completion April 2021) and Phase 1 trials (est. completion December 2021).

If you are interested in investment opportunities please contact us

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