Transcriptional enhanced associate domain (TEAD) transcription factor inhibitors and uses thereof
Inventors
Gray, Nathanael S. • Zhang, Tinghu • Liu, Yao • Fan, Mengyang • Gao, Yang
Assignees
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Publication Number
US-12698259-B2
Publication Date
2026-08-04
Expiration Date
Abstract
Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, compositions, and mixtures thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases (e.g., proliferative diseases (e.g., cancers, such as carcinoma, sarcoma, lung cancer, thyroid cancer, skin cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, esophageal cancer, liver cancer, breast cancer)) in a subject. Provided are methods of inhibiting a TEAD transcription factors (e.g., TEAD1, TEAD2, TEAD3, TEAD4) in a subject.
Core Innovation
The disclosure provides small-molecule compounds and pharmaceutical compositions for inhibiting TEAD transcription factors, specifically identifying TEAD1, TEAD2, TEAD3, and TEAD4. Disclosed compounds covalently bind a cysteine in the central pocket of the TEAD YAP-binding domain to reduce transcription-factor activity. The disclosure includes compounds of the recited formulae and Formula (I-e), encompassing specified heterocyclic rings, linkers, and pharmaceutically acceptable salts or derivatives.
Disclosed embodiments include acrylamide-type warheads, fused bicyclic systems, and flufenamic acid derivatives evaluated for modulating TEAD reporter activity and palmitoylation. The disclosure also provides pharmaceutical compositions, kits, and combinations with anticancer agents to treat proliferative diseases or induce apoptosis. Because abstract, summary, and background sections are absent from the provided partial content, the problem being solved is not explicitly described in patent.
Claims Coverage
The independent claims are claim 1 and claim 12, defining two inventive features covering structurally distinct compound genera and their specified pharmaceutically acceptable forms or derivatives.
Compounds of the recited formulae
Claim 1 covers a compound of any one of the recited formulae, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof. The claim defines structural alternatives for R1, R2, ring A, X1, X2, m, and D1, including specified L3, RE1, RE2, RE3, and Y selections.
Compound of Formula (I-e)
Claim 12 covers a compound of Formula (I-e), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. The claim defines alternatives for R1, R2, ring A, V1, X1, X2, m, and D1, including specified L3, RE1, RE2, RE3, and Y selections.
The two independent claims cover structurally defined compound genera, comprising compounds of the recited formulae and compounds of Formula (I-e), along with recited substituent, ring, and linker alternatives and specified pharmaceutically acceptable forms.
Stated Advantages
Combinations with anticancer agents are stated to synergistically augment TEAD inhibition.
The combinations may address treatment-resistant proliferative diseases.
Documented Applications
Use of the disclosed compounds to inhibit TEAD1-TEAD4 or transcription-factor activity, including by administration or contact with a biological sample.
Treatment or prevention of TEAD-associated proliferative diseases, particularly cancers, including treatment-resistant disease.
Combination use of the disclosed compounds with anticancer agents for proliferative diseases.
Pharmaceutical compositions comprising a claim 1 compound or a specified form or derivative thereof together with a pharmaceutically acceptable excipient.
Pharmaceutical kits for disease treatment, transcription-factor inhibition, and apoptosis induction.
Use of the disclosed compounds as probes.
Assessment of disclosed compounds using TEAD transcription reporter and endogenous-target assays, compound pulldown from MDA-MB-231 lysates, and mass-spectrometric labeling of TEAD2.
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