Chemestmed presentation at the Cold Spring Harbor (USA) meeting “Neurodegenerative Diseases: Biology & Therapeutics” November 30 - December 3, 2022


The CEO Dr. Neinar Seli and Professor Mati Karelson presented Chemestmed’s groundbreaking results on unique proprietary RNA m6A activators in neuroscience titled as “Neuroprotective agents based on RNA m6A regulation”


N6-Methyladenosine (m6A) is the most common cellular modification that occurs in the mRNA of eukaryotes, but also in microRNAs and some small nuclear RNAs. There is increasing evidence about the mRNA m6A methylation dysregulation in the case of neurodegenerative diseases such as PD, AD and ALS, and neuropsychiatric disorders. The m6A formation is mostly catalyzed by a methyltransferase complex containing methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), and Wilm’s-tumor-1-associated protein (WTAP), and monomeric METTL16. The demethylation of m6A is catalyzed by two enzymes: the fat-mass- and obesity-associated protein also known as FTO and the RNA demethylase ALKBH5. By using in silico-based discovery, chemical synthesis and biochemical studies, we had discovered unique small-molecule ligands that bind to and activate RNA m6A methylation through catalytic METTL3/METTL14/WTAP complex.  In addition, we have identified several inhibitors of RNA m6A demethylases FTO and ALkBH5. The best compounds from each of these classes at already 10 nM support the survival of 6-OHDA lesioned DA neurons in culture. Remarkably, the methyltransferase complex METTL3/METTL14/WTAP activator M4 improved motor behavior and protected DA neurons in rat 6-OHDA model of PD much more efficiently than neurotrophic factor GDNF. This is the first demonstration that RNA m6A regulators can protect DA neurons in vitro and in vivo. This observation is supported by our further finding that specific inhibitor of METTL3/14 STM2457 kills DA neurons at low micromolar concentrations. Furthermore, we have also discovered that the systemically administered METTL3/METTL14/WTAP activators are behaviorally active in preclinical in vivo tests for anxiolytic and antidepressant activity, and also displaying a profile of strong anti-apathy action. The strength of the compounds is their unique mode of action and high efficacy. The cytotoxicity screening on the number of endpoints including cell count, nuclear size, DNA structure etc. did not show any significant toxicity of compounds. The compounds have good water solubility, they can pass through the BBB and show no toxicity in vivo. Thus our studies provide preclinical support for the use of compounds regulating the RNA m6A methylation as candidates for the further drug development against PD and neuropsychiatric disorders.