DYRK1A inhibitors(Dual-specificity tyrosine-phosphorylation regulated kinase 1A inhibitors), DYRK1B inhibitors(dual specificity tyrosine phosphorylation regulated kinase 1B inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Squamous Cell Carcinoma of Head and Neck

Inactive Indication-

Originator Organization

Dana-Farber Cancer Institute, Inc.

Active Organization

Dana-Farber Cancer Institute, Inc.

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC22H18F4N8O

InChIKeyYVQOYBIBWBAHKH-UHFFFAOYSA-N

CAS Registry3034312-17-6

100 Clinical Results associated with JH-XVII-10

100 Translational Medicine associated with JH-XVII-10

100 Patents (Medical) associated with JH-XVII-10

Literatures (Medical) associated with JH-XVII-10

23 Mar 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases

Q1 · MEDICINE

Article

Author: Deau, Emmanuel ; Alfonso, Patricia ; George, Nicolas ; Corrionero, Ana ; Arfwedson, Jonas ; George, Pascal ; Lindberg, Mattias F ; Meijer, Laurent

Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) play a large variety of cellular functions and are involved in several diseases (cognitive disorders, diabetes, cancers, etc.). There is, thus, growing interest in pharmacological inhibitors as chemical probes and potential drug candidates. This study presents an unbiased evaluation of the kinase inhibitory activity of a library of 56 reported DYRK/CLK inhibitors on the basis of comparative, side-by-side, catalytic activity assays on a panel of 12 recombinant human kinases, enzyme kinetics (residence time and K_d), in-cell inhibition of Thr-212-Tau phosphorylation, and cytotoxicity. The 26 most active inhibitors were modeled in the crystal structure of DYRK1A. The results show a rather large diversity of potencies and selectivities among the reported inhibitors and emphasize the difficulties to avoid "off-targets" in this area of the kinome. The use of a panel of DYRKs/CLKs inhibitors is suggested to analyze the functions of these kinases in cellular processes.

14 Apr 2022·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Selective Macrocyclic Inhibitors of DYRK1A/B

Q3 · MEDICINE

Article

Author: Vatsan, Prasanna S. ; Jiang, Jie ; Gray, Nathanael S. ; Hatcher, John M. ; Che, Jianwei ; Powell, Chelsea E.

Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a therapeutic target of interest due to the roles it plays in both neurological diseases and cancer. We present the development of the first macrocyclic inhibitors of DYRK1A. Initial lead inhibitor JH-XIV-68-3 (3) displayed selectivity for DYRK1A and close family member DYRK1B in biochemical and cellular assays, and demonstrated antitumor efficacy in head and neck squamous cell carcinoma (HNSCC) cell lines. However, we noted that it suffered from rapid aldehyde oxidase (AO)-mediated metabolism. To overcome this liability, we generated a derivative (JH-XVII-10 (10)), where fluorine was introduced to block the 2-position of the azaindole and render the molecule resistant to AO activity. We showed that 10 maintains remarkable potency and selectivity in biochemical and cellular assays as well as antitumor efficacy in HNSCC cell lines and improved metabolic stability. Therefore, 10 represents a promising new scaffold for developing DYRK1A-targeting chemical probes and therapeutics.

100 Deals associated with JH-XVII-10

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Squamous Cell Carcinoma of Head and Neck	Preclinical	United States	Dana-Farber Cancer Institute, Inc.	14 Apr 2022

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JH-XVII-10

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Translational Medicine

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