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Publication Number
US-11952352-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
Core Innovation
The disclosure relates to structurally defined compounds presented as closely related chemical structure variants with complex multi-ring, heterocyclic, and stereochemically defined scaffolds. The disclosed compounds include multiple chiral centers, amide, urea-like, lactam, ester, acid, carbonyl, sulfur-containing, and heteroaromatic motifs, with substituent variation across the depicted compound families. In some disclosures, the structures are explicitly tied to compound tables, image sets, or labeled embodiments that define the scope of the chemical series.
Several disclosures describe specific structural frameworks using variable substituent and linker definitions, including Formula I, Formula II, Formula III variants, Formula IV, and Formula V. The structural scope includes alternative cross-linking groups, linker frameworks, and substituent ranges, together with stereochemical definitions and optional pharmaceutically acceptable salt coverage. Some disclosures also describe conjugate-related constructs and monovalent organic moieties, including protein moieties such as Ras proteins.
The disclosure also relates to cross-linkable pharmaceutical compounds defined by a detailed structural formula with variable components A, B, L, and W, including stereoisomers and pharmaceutically acceptable salts. W is defined as a cross-linking group selected from vinyl ketone, vinyl sulfone, ynone, or alkynyl sulfone, and the compounds include extensive substitution possibilities via substituent variables. The provided material further includes linker Formula II embodiments and, in some disclosures, Ras-targeted macrocyclic inhibitors, ternary complex or conjugate formation with cyclophilin A, and steric occlusion of Ras effector interactions.
Claims Coverage
Across the consolidated input, the independent claims primarily cover structurally defined compounds and pharmaceutical compositions comprising those compounds or their pharmaceutically acceptable salts together with a pharmaceutically acceptable excipient. The claim coverage repeatedly centers on compound structure definitions, with four independent claims being a common pattern in several items, and on composition claims that add excipient coverage.
Structurally defined compound
A compound of the following structure.
Structurally defined compound and pharmaceutically acceptable salt
A compound of the following structure, or a pharmaceutically acceptable salt thereof.
Cross-linkable compound structure with defined A, B, L, and W
A compound of the following structure, or a pharmaceutically acceptable salt thereof, where the structure is defined by variable components including A, B, L, and W and includes the specified cross-linking group and structural substitution options described in the disclosure.
Pharmaceutical composition with structurally defined compound and excipient
A pharmaceutical composition comprising a compound of the following structure and a pharmaceutically acceptable excipient.
Pharmaceutical composition with structurally defined compound, salt, and excipient
A pharmaceutical composition comprising a compound of the following structure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
Pharmaceutical composition including the defined cross-linkable compound and an excipient
A pharmaceutical composition comprising a compound of the following structure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutically acceptable excipient.
Overall, the claim coverage is centered on specific chemical structures, often with optional pharmaceutically acceptable salt coverage, and on pharmaceutical compositions that include the defined compounds together with a pharmaceutically acceptable excipient. In some disclosures, the structural scope is further expressed through variable linker, cross-linking group, conjugate, and stereochemical definitions.
Stated Advantages
Provides assay data supporting KRAS-mutant target engagement.
Shows anticancer potency for compounds of the present invention.
Demonstrates in vivo xenograft efficacy in NSCLC KRAS G12C with Compound A alone.
Supports combination efficacy with cobimetinib or an SHP2 inhibitor, including tumor regression outcomes.
Supports sustained growth inhibition in vitro with MEK inhibitor (trametinib) plus Compound D.
Steric occlusion of Ras effector interactions, including RAF and PI3K.
Ras inhibition via ternary complex/conjugate formation.
Utility in pharmaceutical compositions for treatment of cancer and Ras-related disorders.
Documented Applications
KRAS-mutant target engagement characterization using FRET tables for KRAS and NRAS panels.
Assessment of anticancer potency via cell proliferation and IC50 summaries across multiple cancer cell lines.
In vivo NSCLC KRAS G12C xenograft efficacy of Compound A alone.
In vivo combination regimens including Compound A with cobimetinib or an SHP2 inhibitor, with reported tumor regression outcomes.
In vitro confluence assay showing that trametinib plus Compound D yields sustained growth inhibition.
Treatment methods for cancer.
Treatment methods for Ras protein-related disorders.
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