WDR5 inhibitors and modulators
Inventors
Lee, Taekyu • HAN, Changho • Mills, Jonathan J. • Teuscher, Kevin B. • TIAN, Jianhua • MEYERS, Kenneth M. • Chowdhury, Somenath • Fesik, Stephen W.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12577227-B2
Publication Date
2026-03-17
Expiration Date
Abstract
Quinazolin-4(3H)-one, 2,3-dihydroquinazolin-4(1H)-one, 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one, and 3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione compounds and derivatives inhibit WDR5 and associated protein-protein 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
A compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. The compound is defined by a structural framework including R1, G1, L, X, G2, and multiple substituents, with specified ring sizes, optional fusion patterns, and optional substitution classes for G1 and G2. The scaffold includes linkage variants in which L is a carbon-based linking unit or a double-bond form, with X selected from O, NR3, S, or N depending on the case.
G1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C3-10 carbocycle optionally fused to a phenyl or to a 5- to 6-membered heteroaryl. G1 is optionally substituted with 1-5 substituents selected from halogen, C1-6 alkyl, C1-6 haloalkyl, oxo, —OR1a, —N(R1a)2, —SR1a, cyano, carbonyl-, sulfinyl-, and sulfonyl-containing groups, and —L1-G1a. G2 is likewise defined as a carbocycle, aryl, heteroaryl, or heterocycle with comparable optional substitution patterns and linked group options.
The disclosure further characterizes the scaffold through additional variables including X1, X2, t, R5, R6, R7a, R7b, R8, and other residue classes. R8 is specified as indolyl, pyrrolopyridinyl, or imidazolyl, optionally substituted as defined, and the description includes alternative formula representations and dependent refinements across the same overall compound family. The compounds are also presented in examples as substituted small-molecule analogs, with characterization by LCMS and NMR reported for representative members.
Claims Coverage
The provided material centers on one independent compound claim covering a broad formula (I) scaffold with extensive structural constraints and optional substitution patterns; dependent refinements narrow particular substituent choices and alternative structural representations. The inventive features combine the defined formula (I) compound or pharmaceutically acceptable salt with specific choices for ring systems, linker forms, heteroatom selection, and substituent classes.
Compound of formula (I) or pharmaceutically acceptable salt
A compound of formula (I) or a pharmaceutically acceptable salt thereof, with R1, G1, L, X, G2, and other variables constrained by defined ring-size, heteroatom, and substitution options.
Defined G1 ring system and optional substitution
G1 is selected from aryl, heteroaryl, heterocyclyl, or fused carbocycle motifs and is optionally substituted with 1-5 substituents from the listed classes, including —L1-G1a.
Linker and heteroatom selection
L is defined as a carbon-based linkage or a double-bond form, with X selected as O, NR3, S, or N according to the stated case, and X1 and X2 further defined within the scaffold.
Defined G2 ring system and substituent classes
G2 is independently selected from carbocycle, aryl, heteroaryl, or heterocycle options and is optionally substituted with the listed substituent classes.
Specific residue options including R8
R8 is indolyl, pyrrolopyridinyl, or imidazolyl, optionally substituted with the defined groups, and other residue variables are constrained as stated.
Cancer treatment by administering the compound or salt
A method for treating cancer by administering to a subject in need a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt of that compound.
Claim coverage is directed to a highly specified formula (I) compound family with broad but defined structural variability across rings, linkers, heteroatoms, and substituents, together with a cancer-treatment use claim by administration of the claimed compound or its pharmaceutically acceptable salt.
Stated Advantages
Binding to WDR5 with reported Ki values, including very low Ki ranges down to about 0.01 nM.
Targeting of WDR5/MLL1.
Treating or inhibiting cancer via administration.
Inhibiting cancer cell proliferation.
Inhibits WDR5 binding.
Inhibits WDR5 interactions with chromatin and regulators, including MLL1.
Supports treatment of WDR5-dependent cancers, including leukemia.
Exhibits antiproliferative effects in MLL-relevant cell lines.
Provides pharmaceutical composition and method embodiments, including therapeutically effective amount language.
Documented Applications
Pharmaceutical compositions.
Methods for treating or inhibiting cancer by administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Methods for inhibiting cancer cell proliferation via administration of the compound or salt.
WDR5/MLL1 targeting, supported by reported WDR5 binding and Ki values.
Inhibition of WDR5 binding relevant to the WDR5–MLL1 protein-protein interaction and WDR5 WIN site.
Treatment of WDR5-dependent cancers, including leukemia.
Use in MLL-relevant cell lines to measure antiproliferative activity.
Interested in licensing this patent?