FRTX-02, a selective and potent inhibitor of DYRK1A, modulates inflammatory pathways in mouse models of psoriasis and atopic dermatitis

Kim, Soochan; Ko, Eunhwa; Choi, Hwan Geun; Kim, Daekwon; Luchi, Monica; Khor, Bernard; Kim, Sunghwan

doi:10.1016/j.jtauto.2022.100185

Cited by 1 publication

(1 citation statement)

References 55 publications

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“…Despite these efforts, research on in vivo disease models has not made significant progress, largely due to limited pharmacokinetics (PK) characteristics, low ligand utilization rate, or poor selectivity of reported small molecule inhibitors for DYRK1A. So far, several small molecules have been studied in clinical trials: Epigallocatechin gallate (EGCG) and lorecivivint are currently in phase III trials (Figure ), while others such as SM07883 and BBI02 (structures of SM07883 and BBI02 not disclosed) are in phase I trials. The difference is that the other three small molecules are ATP-competitive inhibitors, while EGCG is an ATP-noncompetitive inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer’s Disease

Chen,

Gao,

et al. 2024

J. Med. Chem.

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Targeting dual-specificity tyrosine phosphorylationregulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC 50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood−brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.

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Section: Introductionmentioning

confidence: 99%