WDR5-MYC inhibitors
Inventors
Chacon Simon, Selena • Waterson, Alex • Macdonald, Jonathan D. • Fesik, Stephen • Stauffer, Shaun R. • Tansey, William P.
Assignees
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Publication Number
US-12545649-B2
Publication Date
2026-02-10
Expiration Date
Abstract
Substituted N-heteroaryl sulfonamide compounds inhibit WDR5-MYC interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject such as cancer cell proliferation.
Core Innovation
The patent describes substituted N-heteroaryl sulfonamide compounds as compounds of formula (I), or pharmaceutically acceptable salts thereof, with extensive structural variation through group variables G, R1a, R1b, R1c, Q, G1, G2, and related substituent classes. The structures include sulfonamide compounds with a 5-bromo-3-chloro-2-hydroxybenzenesulfonamide core, imidazole-containing sulfonamide cores, and substituted benzenesulfonamide derivatives bearing halogen, hydroxy, alkyl, haloalkyl, oxo, cyano, heterocycle, and heteroaryl groups.
The disclosure states that the compounds inhibit the WDR5–MYC interaction by binding the WDR5 WBM site, thereby preventing MYC binding to WDR5, inhibiting MYC recruitment to chromatin, and disrupting MYC-governed oncogenic processes. The problem addressed is the MYC–WDR5 protein-protein interaction mediated by the MYC box (MbIIIb) and the WDR5 binding motif (WBM site), and the compounds are presented as inhibitors of MYC association with WDR5.
The examples illustrate preparation of imidazole-containing building blocks, conversion into imidazol-4-aminium chloride, and coupling with substituted benzenesulfonyl chloride to yield sulfonamide products. The examples and supporting chemistry include brominated and chlorinated substituted benzenesulfonamides bearing hydroxy substitution and N-substituted imidazole groups, including cycloalkyl- and heteroaryl-substituted imidazole variants.
Claims Coverage
The claims coverage is anchored on a broadly defined Formula (I) compound family with pharmaceutically acceptable salts and a pharmaceutical composition with a pharmaceutically acceptable carrier. Across the inputs, the inventive features include the Formula (I) scaffold with variable substituent and ring definitions, specific enumerated embodiments, refinement of substituent and ring definitions, and a claim where R8 is halogen.
Compound of formula (I) and pharmaceutically acceptable salts
A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein G, R1a, R1b, R1c, Q, G1, G2, X2, R6, R7, R8, R9, R10, and Rb are defined by the listed classes and substitution patterns.
Specified heteroaryl and substituted embodiments
A compound of formula (I), or a pharmaceutically acceptable salt thereof, corresponding to enumerated substituted embodiments including halogenated benzenesulfonamide-linked imidazole-containing heterocycles and related heteroaryl sulfonamide structures.
Substituent and ring definition refinement
A compound of formula (I), or a pharmaceutically acceptable salt thereof, with specified substituent definitions for R1a, R1b, R1c, G1, and G2, including optional substitution patterns and ring-size ranges.
R8 is halogen
A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R8 is halogen.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claims coverage centers on a broadly defined Formula (I) compound class with extensive substituent and ring-group variability, narrows to specific substituted embodiments and refinements including R8 as halogen, and includes pharmaceutical composition coverage with a pharmaceutically acceptable carrier.
Stated Advantages
Inhibiting binding of MYC to WDR5.
Blocking MYC recruitment to chromatin.
Inhibiting MYC-governed oncogenic processes.
The disclosed compounds bind WDR5 to inhibit MYC association.
Reported Ki values include values down to about 0.01 nM.
Targets MYC/WDR5 interaction with protein-protein interaction disruption supported by fluorescence polarization Ki and co-immunoprecipitation/ChIP disruption assays, and by MLL histone methyltransferase inhibition assays.
Documented Applications
Therapeutic use for MYC-related cancers, including multiple solid tumors and cancers of the blood and lymphatic system.
Cancer types explicitly referenced include ovarian cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, stomach cancer, lung cancer, cervical cancer, and uterine cancer.
Use in inhibiting MYC association by binding WDR5.
Methods of treatment targeting MYC/WDR5 interaction disruption.
Pharmaceutical composition formulation including the compound with pharmaceutically acceptable carriers.
Preparation and analytical characterization of substituted heterocyclic sulfonamide compounds of Formula (I), including examples of 5-bromo-3-chloro-2-hydroxybenzenesulfonamide derivatives with N-substituted imidazole groups.
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