WD40 repeat domain protein 5 (WDR5) degradation/disruption compounds and methods of use
Inventors
Jin, Jian • Wang, Gang • Liu, Jing • Yu, Xufen • LI, DONGXU
Assignees
University of North Carolina at Chapel Hill • Icahn School of Medicine at Mount Sinai
Publication Number
US-12110295-B2
Publication Date
2024-10-08
Expiration Date
2039-06-21
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Abstract
Disclosed herein are WD40 repeat domain protein 5 (WDR5) degradation/disruption compounds including a WDR5 ligand, a degradation/disruption tag, and a linker, and methods of using such compounds in the treatment of WDR5-mediated diseases.
Core Innovation
The invention relates to bivalent compounds comprising a WDR5 ligand conjugated to a degradation or disruption tag via a linker, which mediate degradation or disruption of WDR5. Unlike prior WDR5 inhibitors that only inhibit protein-protein interactions, these compounds promote the elimination of WDR5 protein itself, removing all associated functions. The compounds consist of three components: a WDR5 ligand (e.g., OICR-9429), a degradation/disruption tag (e.g., pomalidomide or VHL ligands), and a linker connecting them.
Claims Coverage
The patent claims cover bivalent compounds targeting WDR5, methods for treating WDR5-mediated diseases, and procedures for identifying WDR5 degraders, focusing on their mechanisms of degradation or disruption.
Bivalent compound structure
A compound combining a WDR5 ligand with a degradation/disruption tag through a specific linker.
Therapeutic application methods
Administering these compounds to treat diseases related to WDR5, such as various cancers including leukemia, ovarian, gastric, colorectal, lung, pancreatic, bladder, breast cancers, and neuroblastoma.
Identification methods for WDR5 degraders
Use of cell-based assays involving WDR5 and ubiquitin ligases to screen and identify compounds that induce WDR5 degradation.
Specific compound claims
Claims covering particular bivalent compounds, including those exemplified with structures disclosed in the patent's tables.
The claims comprehensively protect the structure of WDR5-targeting bivalent degraders, their therapeutic use in cancer treatment, and the methods for their identification, emphasizing the link of WDR5 ligands to degradation tags via specific linkers.
Stated Advantages
The bivalent WDR5 degraders surpass traditional inhibitors by effectively inducing WDR5 protein degradation, removing its scaffolding functions rather than merely blocking interactions.
They exhibit potent, selective degradation of WDR5 in cancer cells at low concentrations, with effects dependent on time and dosage.
These degraders more effectively reduce cancer cell viability and proliferation compared to existing inhibitors like OICR-9429.
The linker design permits flexible and controllable regulation of protein degradation, enabling dose- and time-dependent effects.
Documented Applications
Treating WDR5-mediated cancers including leukemia, lymphoma, ovarian, gastric, colorectal, lung, pancreatic, bladder, breast cancers, and neuroblastoma.
Using the compounds through various administration routes such as oral, injection, topical, or rectal in patients with relevant diseases.
Employing cell-based assays with ubiquitin ligases and WDR5 protein to identify small molecule degraders or disruptors of WDR5.
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