DYRK / CLK protacs and uses thereof

Bifunctional PROTAC compounds targeting DYRK1 kinases provide a novel therapeutic approach by degrading these enzymes, addressing the limitations of current treatments for Alzheimer’s, cancer, and other diseases by inhibiting WNT signaling and reducing kinase activity.

WO2025080753A1 Publication Date: 2025-04-17THE ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIV OF ARIZONA +1
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Patent Information

Application Number
PCT/US2024/050636
Authority / Receiving Office
WO · WO
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-10-10
Filing Date
2024-10-10
Publication Date
2025-04-17

AI Technical Summary

Technical Problem

Current treatments for Alzheimer’s disease, Down syndrome, diabetes, autoimmune diseases, inflammatory disorders, and various cancers lack effective inhibitors for DYRK1A and DYRK1B kinases, which are associated with neurodegeneration, tumor progression, and immune homeostasis.

Method used

Development of bifunctional PROTAC compounds that combine a small molecule inhibitor of DYRK1 kinases with an E3 ubiquitin ligase binding moiety, specifically targeting DYRK1A, DYRK1B, and other related kinases for degradation, thereby inhibiting WNT signaling.

Benefits of technology

The PROTAC compounds efficiently degrade DYRK1 kinases, leading to reduced kinase activity and sensitization of cancer cells to cisplatin, offering potential therapeutic benefits for various diseases including Alzheimer’s, cancer, and inflammatory disorders.

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Abstract

The present invention relates to bifunctional compounds, which find utility to degrade and (inhibit) one or more of the following kinases: DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, HIPKs, and / or CMGC kinases leading to inhibition of WNT signaling. In particular, the present invention is directed to compounds, which contain on one end an E3 ubiquitin ligase binding moiety which binds to an E3 ubiquitin ligase and on the other end a moiety which binds one or more of the following kinases: DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, CLK1, CLK2, CLK3, CLK4, CDK7, CDK8 / 19, PI3K, PDGFrA / B, mTOR, HIPKs, and / or CMGC kinases leading to inhibition of WNT signaling, such that the one or more kinases is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the one or more kinases. The bifunctional compounds serve as therapeutics for the treatment of Alzheimer's disease, down syndrome, diabetes, an autoimmune disease, an inflammatory disorder (e.g., airway inflammation, osteoarthritis (e.g., knee related osteoarthritis)), cancer (e.g., glioblastoma, prostate cancer, metastatic breast cancer, metastatic lung cancer, multiple myeloma, secondary metastatic tumors of the brain, colorectal cancer, acute myeloid leukemia, myelodysplastic syndrome), a viral infection (e.g., SARS-CoV-2 infection (e.g., COVID-19)), and other diseases.
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