Therapeutics

Leucettinib-21

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Overview

Name: Leucettinib-21
Synonyms: (R,Z)-5-(benzo[d]thiazol-6-ylmethylene)-2-((1-methoxy-4-methylpentan-2-yl)amino)-3,5-dihydro-4H-imidazol-4-one
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Down's Syndrome
U.S. FDA Status: Alzheimer's Disease (Phase 1), Down's Syndrome (Phase 1)
Company: Perha Pharmaceuticals

Background

Leucettinib-21 is a small-molecule inhibitor of the dual-specific, tyrosine phosphorylation-regulated kinase DYRK1A (Lindberg and Meijer 2021). Abnormally active DYRK1A has been implicated in memory and learning problems in Alzheimer’s disease and Down's syndrome. Taken in tablet form, this drug is claimed to cross the blood-brain barrier.

Dyrk1 has been found to regulate alternative splicing of tau exon 10 (Qian et al., 2011; Yin et al., 2012). For a review of tau isoforms in Alzheimer’s and related diseases, see Buchholz and Zempel, 2024).

In AD, proteases cleave full-length DYRK1A into a more stable and active kinase. Many substrates have been identified, including tau at residue 212 (Kimura et al., 2007), but also APP, presenilin, and other synaptic and cytoskeletal proteins. Excess DYRK1A activity has been shown to dysregulate tau splicing to favor the 3R isoform (Yin et al., 2017).

In Down's syndrome, DYRK1A is overexpressed due to the presence of the gene in the trisomy region of chromosome 21.

Pharmacological or genetic inhibition of DYRK1A has been reported to reduce pathology or improve cognition in AD and DS rodent models (e.g. Velazquez et al., 2019; Branca et al.., 2017; see Meijer et al., 2024 for comprehensive listing).

Leucettinib-21 was derived by medicinal chemistry optimization of the marine sponge natural product Leucettamine B (Deau et al., 2023; reviewed in Meijer et al., 2024). It inhibits DYRK1 with a 2.4 nM IC50. The compound was reported to correct memory deficits in the Down's syndrome mouse model Ts65Dn (Lindberg et al., 2023).

Findings

In January 2024, Phase 1 began with a four-part study to assess safety after single and multiple doses in healthy men, food effects, as well as safety of single doses in men with Down’s syndrome and Alzheimer’s disease. The placebo-controlled trial involves 120 participants, at one study site near Grenoble, France. Healthy men are to receive 5, 10, 30, 60, or 120 mg doses, 40 mg with or without a high fat meal, or multiple doses of 60 or 120 mg per day for 14 days. Twelve men with Down’s syndrome and 12 with AD are to receive a single, 60 mg dose. Primary outcomes are safety and tolerability and, in the food study, plasma pharmacokinetics. Secondary outcomes include pharmacokinetics, protein phosphorylation, and DYRK1 activity in blood after treatment. Other biomarkers include pTau212 and pTau217. The study was planned to end in August 2024.

First results were presented at the October 2024 CTAD conference. Doses of 10, 30, or 60 mg in healthy men resulted in blood levels exceeding the IC50 for DYRK1A; the drug persisted for 3.5 hours at the highest dose.

For details on Leucettinib-21 trials, see clinicaltrials.gov.

Last Updated: 29 Jan 2025

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References

Paper Citations

  1. Lindberg MF, Meijer L. Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview. Int J Mol Sci. 2021 Jun 3;22(11) PubMed.
  2. Qian W, Liang H, Shi J, Jin N, Grundke-Iqbal I, Iqbal K, Gong CX, Liu F. Regulation of the alternative splicing of tau exon 10 by SC35 and Dyrk1A. Nucleic Acids Res. 2011 Aug;39(14):6161-71. PubMed.
  3. Yin X, Jin N, Gu J, Shi J, Zhou J, Gong CX, Iqbal K, Grundke-Iqbal I, Liu F. Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Modulates Serine/Arginine-rich Protein 55 (SRp55)-promoted Tau Exon 10 Inclusion. J Biol Chem. 2012 Aug 31;287(36):30497-506. PubMed.
  4. Buchholz S, Zempel H. The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes. Alzheimers Dement. 2024 May;20(5):3606-3628. Epub 2024 Mar 31 PubMed.
  5. Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H, Hashimoto R, Tanaka T, Kudo T, Yamagata H, Tabara Y, Miki T, Akatsu H, Kosaka K, Funakoshi E, Nishitomi K, Sakaguchi G, Kato A, Hattori H, Uema T, Takeda M. The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease. Hum Mol Genet. 2007 Jan 1;16(1):15-23. PubMed.
  6. Yin X, Jin N, Shi J, Zhang Y, Wu Y, Gong CX, Iqbal K, Liu F. Dyrk1A overexpression leads to increase of 3R-tau expression and cognitive deficits in Ts65Dn Down syndrome mice. Sci Rep. 2017 Apr 4;7(1):619. PubMed.
  7. Velazquez R, Meechoovet B, Ow A, Foley C, Shaw A, Smith B, Oddo S, Hulme C, Dunckley T. Chronic Dyrk1 Inhibition Delays the Onset of AD-Like Pathology in 3xTg-AD Mice. Mol Neurobiol. 2019 Dec;56(12):8364-8375. Epub 2019 Jun 25 PubMed.
  8. Branca C, Shaw DM, Belfiore R, Gokhale V, Shaw AY, Foley C, Smith B, Hulme C, Dunckley T, Meechoovet B, Caccamo A, Oddo S. Dyrk1 inhibition improves Alzheimer's disease-like pathology. Aging Cell. 2017 Oct;16(5):1146-1154. Epub 2017 Aug 4 PubMed.
  9. Meijer L, Chrétien E, Ravel D. Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer's Disease and Down Syndrome. J Alzheimers Dis. 2024;101(s1):S95-S113. PubMed. Correction.
  10. Deau E, Lindberg MF, Miege F, Roche D, George N, George P, Krämer A, Knapp S, Meijer L. Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B. J Med Chem. 2023 Aug 10;66(15):10694-10714. Epub 2023 Jul 24 PubMed.
  11. Lindberg MF, Deau E, Miege F, Greverie M, Roche D, George N, George P, Merlet L, Gavard J, Brugman SJ, Aret E, Tinnemans P, de Gelder R, Sadownik J, Verhofstad E, Sleegers D, Santangelo S, Dairou J, Fernandez-Blanco Á, Dierssen M, Krämer A, Knapp S, Meijer L. Chemical, Biochemical, Cellular, and Physiological Characterization of Leucettinib-21, a Down Syndrome and Alzheimer's Disease Drug Candidate. J Med Chem. 2023 Dec 14;66(23):15648-15670. Epub 2023 Dec 5 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

No Available Further Reading