Inhibitors of YAP/TAZ-TEAD oncoproteins, synthesis and use thereof
Inventors
Zhang, Chao • Bishop, Michael J. • Chen, Hang • Cao, Ping
Assignees
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Publication Number
US-12583815-B2
Publication Date
2026-03-24
Expiration Date
Abstract
Disclosed herein are synthesis and use of covalent inhibitors selective for Transcriptional Enhancer Factor TEF-1 (TEAD1), which can be used for treatment of cancers such as glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma (PDAC), and malignant pleural mesothelioma (MPM). Further disclosed herein are pharmaceutical compositions including the TEAD1 inhibitor and methods of treating cancers using the same.
Core Innovation
The invention relates to a compound according to Formula (I), including an optically pure stereoisomer, or a pharmaceutically acceptable salt or solvate thereof. The compound is defined by Ring2 selected from A—O—(CH2)p—, with R2 and R3 specified within the disclosed scope, and with m is 1, n is 0, and p is an integer selected from 0 to 3. The disclosure also describes broader structural formulae, multiple substituent definitions, representative compound embodiments, and structural drawings and example compounds.
The disclosure further describes covalent TEAD1 inhibitor compounds and TEAD1-selective inhibitors within the same Formula (I) framework. The compounds are positioned for cancer therapy in the Hippo pathway context, and the description also includes pharmaceutical compositions and pharmaceutically acceptable forms.
The document additionally reports biological evaluation using a TEAD1-Luciferase reporter assay and presents IC50 classification for many disclosed compounds. It also includes preparation and characterization of substituted anilide/acrylamide and related intermediates, together with analytical characterization such as 1H NMR and LCMS/ESI MS.
Claims Coverage
The consolidated claim coverage centers on a Formula (I) compound class, including optically pure stereoisomers and pharmaceutically acceptable salts or solvates, with dependent coverage for pharmaceutical formulation and cancer-treatment methods. Across the claim family, the main inventive features are the defined Ring 2 framework, the specified substituents R2 and R3, and the constrained parameter values m = 1, n = 0, and p = 0–3.
Formula (I) compound defined by Ring 2 and substituent constraints
A compound according to Formula (I), or an optically pure stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein Ring 2 is selected from A—O—(CH2)p—, R2 is specified within the disclosed scope, R3 is CF3, n is 0, m is 1, and p is an integer selected from 0 to 3.
Pharmaceutical formulation with a pharmaceutically acceptable carrier
A pharmaceutical formulation including the compound according to the preceding claim together with a pharmaceutically acceptable carrier.
Cancer treatment by administering an effective amount
A method for treating cancer by administering an effective amount of the compound to a subject.
Cancer indication narrowed to selected cancer types
The method further specifies cancer selected from glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma, or malignant pleural mesothelioma.
Combination or timing with a chemotherapeutic agent
The method further includes administering the compound before, at the same time as, or after administering a chemotherapeutic agent.
Overall, the claims cover a structurally defined Formula (I) compound, pharmaceutical formulations containing the compound, and cancer-treatment methods using administration of an effective amount. Dependent claims narrow the therapeutic use to specified cancer types and to combination or sequence-based administration with a chemotherapeutic agent.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cancer therapy using TEAD1-selective inhibitors, including treatment of glioblastoma, gastric cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and malignant pleural mesothelioma.
Pharmaceutical compositions containing the disclosed compounds.
Treatment of cancer by administering an effective amount of the compound to a subject.
Combination-treatment context where the compound is administered before, at the same time as, or after a chemotherapeutic agent.
Preparation and characterization of substituted anilide/acrylamide and related intermediates.
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