Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer’s Disease and Down Syndrome

Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry

Article type: Review Article

Authors: Meijer, Laurent^{a; *} | Chrétien, Emilie^a | Ravel, Denis^b

Affiliations: [a] Perha Pharmaceuticals, Hôtel de Recherche, Roscoff, Bretagne, France | [b] Initial R&D Consulting, Paris, France

Correspondence: [*] Correspondence to: Laurent Meijer, Perha Pharmaceuticals, Hôtel de Recherche, Presqu’île de Perharidy, 29680 Roscoff, Bretagne, France. E-mail: [email protected]; ORCID: 0000-0003-3511-4916.

Abstract: Alzheimer’s disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, DYRK1A is overexpressed due to the presence of the DYRK1A gene on chromosome 21. In AD, calcium-activated calpains cleave full-length DYRK1A (FL-DYRK1A) into a more stable and more active, low molecular weight, kinase (LMW-DYRK1A). Genetic and pharmacological experiments carried out with animal models of AD and DS strongly support the idea that pharmacological inhibitors of DYRK1A might be able to correct memory/learning disorders in people with AD and DS. Starting from a marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, and extensively characterized a small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies in rats and minipigs have been completed and formulation of Leucettinib-21 has been optimized as immediate-release tablets. Leucettinib-21 is now undergoing a phase 1 clinical trial (120 participants, including 12 adults with DS and 12 patients with AD). The therapeutic potential of DYRK1A inhibitors in AD and DS is presented.

Keywords: Alzheimer’s disease, cognitive disorders, Down syndrome, DYRK1A, learning, Leucettinib-21, Leucettinibs, protein kinase

DOI: 10.3233/JAD-240078

Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S95-S113, 2024