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Publication Number
US-11925651-B2
Publication Date
2024-03-12
Expiration Date
Abstract
The present invention provides compounds, compositions thereof, and methods of using the same.
Core Innovation
The invention relates to a method for treating cancer in a patient by administering a compound of Formula I or a pharmaceutically acceptable salt thereof. Formula I is defined by structural constraints on L, Ring A, Ring B via Rw = -L-Y, and substituents Y, Re, Q, and Z, with Ring A as optionally substituted phenyl and Ring B optionally substituted.
L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain with optional replacement of methylene units by heteroatom-containing and functional-group-containing linkages, including oxygen-, nitrogen-, sulfur-, carbonyl-, sulfonyl-, and thiocarbonyl-related motifs. Y is hydrogen, an optionally substituted C1-6 aliphatic group, or a 3-10 membered monocyclic or bicyclic ring system with 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur and substituted with 1-4 Re groups.
Each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, or an optionally substituted C1-6 aliphatic group, where Q is a covalent bond or a bivalent C1-6 saturated or unsaturated hydrocarbon chain with optional heteroatom-containing replacements and Z is hydrogen or an optionally substituted C1-6 aliphatic group. The disclosed embodiments include multiple illustrated compound series and dependent-claim refinements tied to TEAD expression or activity and YAP nuclear localization.
Claims Coverage
The provided material identifies one independent claim directed to treating cancer by administering a Formula I compound or pharmaceutically acceptable salt. The inventive scope is defined by the structural framework of Formula I and its linkage and substituent constraints, with dependent claims further narrowing the cancer context and specific structural embodiments.
Administering a Formula I cancer therapeutic compound or salt
A method for treating cancer in a patient by administering to the patient a compound of Formula I or a pharmaceutically acceptable salt thereof.
Defined linker L with optional heteroatom and functional group replacements
L is a covalent bond or a bivalent C1-8 saturated or unsaturated, straight or branched hydrocarbon chain in which one, two, or three methylene units are optionally and independently replaced by oxygen-, nitrogen-, sulfur-, carbonyl-, sulfonyl-, and thiocarbonyl-related linkages.
Ring A optionally substituted phenyl
Ring A is optionally substituted phenyl.
Ring B via Rw = -L-Y
Ring B is optionally substituted and Rw is defined as -L-Y, with Y being hydrogen, an optionally substituted C1-6 aliphatic group, or a 3-10 membered monocyclic or bicyclic ring system with 0-3 heteroatoms and 1-4 Re groups.
Re, Q, and Z substituent framework
Each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, or an optionally substituted C1-6 aliphatic group; Q is a covalent bond or a bivalent C1-6 saturated or unsaturated hydrocarbon chain with optional heteroatom-containing replacements; and Z is hydrogen or an optionally substituted C1-6 aliphatic group.
Cancer associated with increased TEAD expression or activity
Dependent claims further specify cancer associated with increased TEAD expression and/or increased TEAD activity, including increased expression and/or activity of TEAD1, TEAD2, TEAD3, and/or TEAD4.
Cancer with YAP nuclear localization
Dependent claims further specify a cancer in which YAP is localized in the nucleus of the cancer cells.
Overall, the claim coverage centers on a cancer treatment method that administers a Formula I compound or salt defined by detailed constraints on L, Ring A, Ring B through Rw = -L-Y, and the Re/Q/Z substituent framework, with dependent claims narrowing the treatment to TEAD- and YAP-associated cancer contexts.
Stated Advantages
Selective inhibition by disrupting the YAP/TAZ-TEAD interaction.
Prevention of TEAD palmitoylation.
Inhibition of proliferation of Hippo/NF2-deficient cancer cells but not Hippo wild-type cancer cells.
Downregulation of YAP-dependent genes in human tumor xenografts after oral dosing.
Single-agent tumor growth inhibition at well-tolerated doses.
No deleterious effects in differentiated mouse podocytes and associated mouse kidney histology.
TEAD inhibition and modulation of the TEAD/YAP/TAZ pathway in cancer treatment.
Documented Applications
Treating cancer in a patient by administering a compound of Formula I or a pharmaceutically acceptable salt thereof.
Treating Hippo-pathway-driven cancers in a patient by administering TEAD inhibitor compounds of Formula I or salts.
Use in human tumor xenografts showing downregulation of YAP-dependent genes and single-agent tumor growth inhibition after oral dosing.
Safety-related observation in differentiated mouse podocytes and mouse kidney histology showing no deleterious effects.
Pharmaceutical composition/formulation concepts for TEAD inhibitors.
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