Ras inhibitors
Inventors
Aggen, James • Burnett, G. Leslie • Pitzen, Jennifer • Gill, Adrian L. • Koltun, Elena S. • Cregg, James • BUCKL, Andreas • Edwards, Anne V. • Knox, John E.
Assignees
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Publication Number
US-11739074-B2
Publication Date
2023-08-29
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. Exemplary Ras inhibitors include compounds of Formula I:
Core Innovation
The disclosure relates to macrocyclic Ras inhibitor compounds of Formula I, including Formula Ia, Formula Ib, and Formula Ic, and to compounds represented by multiple specific chemical structures selected from defined groups, including compound or pharmaceutically acceptable salt forms. The structures share common complex scaffolds with multiple amide, urea-like, and carboxylate motifs, stereochemical annotations, and varying heterocyclic, heteroaryl, and cyclic substituent patterns.
The macrocyclic Ras inhibitor compounds form high-affinity ternary complexes with Ras and cyclophilin A (CYPA), generating a new Ras binding pocket and inhibiting Ras signaling by steric occlusion of Ras-effector interactions. The disclosure also refers to variable substituents defined using groups including A, B, G, L, W, X1-X3, Y1-Y7, and multiple R groups, with cross-linking group W defined in terms of multiple linking options including carbodiimide, oxazoline, thiazoline, chloroethyl urea, thiourea, carbamate, thiocarbamate, aziridine, EEDQ/iso-EEDQ, epoxide, oxazolium, glycal, and boronic acid/ester.
Additional content provides synthetic routes to chiral aziridine-containing amino-acid intermediates, azaspiro[4.4]nonane-containing amide/aziridine carboxamide derivatives, and chiral peptidomimetic analogs built around fused bicyclic heterocycle cores. Scheme 5, Scheme 6, and Scheme 7 describe macrocycle construction and related derivatization or deprotection steps as part of the disclosed chemical series.
Claims Coverage
The consolidated claim coverage centers on a compound, or a pharmaceutically acceptable salt thereof, selected from a defined group, with dependent refinement to a pharmaceutical composition including a pharmaceutically acceptable excipient. Across the provided items, the independent claim themes merge into two recurring inventive features, with a related macrocyclic Ras inhibitor compound selected from a defined group.
Selected compound or pharmaceutically acceptable salt
A compound, or a pharmaceutically acceptable salt thereof, selected from a defined group of disclosed members.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the selected compound, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.
Macrocyclic Ras inhibitor compound
A macrocyclic Ras inhibitor compound, or a pharmaceutically acceptable salt thereof, selected from a defined group.
Overall, the claim coverage is directed to selected compounds or pharmaceutically acceptable salts from defined groups, with dependent coverage for pharmaceutical compositions containing a pharmaceutically acceptable excipient. The additional explicit claim-level theme is the macrocyclic Ras inhibitor compound selected from a defined group.
Stated Advantages
Inhibits Ras signaling by steric occlusion of Ras-effector interactions.
Forms a high-affinity ternary complex with Ras and cyclophilin A (CYPA), generating a new Ras binding pocket.
Provides therapeutic treatment of cancers and Ras-related disorders using the disclosed Ras inhibitors.
Documented Applications
Treating cancer by Ras inhibition, including Ras WT and Ras amplification (Ras amp) and specific Ras mutants such as K-Ras G12C/G12D/G12V; H-Ras Q61R/Q61L; and N-Ras Q61K/Q61R/G12C.
Therapeutic methods for treating cancers and Ras-related disorders using the disclosed compounds.
Use in Ras signaling inhibition involving Ras-effector interactions and Ras/CYPA ternary complex formation.
Use of the disclosed compounds in biological evaluation contexts involving KRAS variant assays and cell viability outcomes in RAS mutant cancer cell lines.
Use as pharmaceutical compositions and dosage forms for administering a therapeutically effective amount, including mention of dosing regimen language.
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