Ras inhibitors
Inventors
Knox, John E. • Koltun, Elena S. • Liu, Yang • Burnett, G. Leslie • Cregg, James • Edwards, Anne V. • Gill, Adrian L. • BUCKL, Andreas • Semko, Christopher
Assignees
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Publication Number
US-12202845-B2
Publication Date
2025-01-21
Expiration Date
Abstract
The invention 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 invention relates to compounds having the structure of Formula I and pharmaceutically acceptable salts thereof. In Formula I, A is morpholine-diyl, X1, X2, and X3 are each CH2, m is 1, and n is 1. R1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is cyclopentyl.
The disclosure also presents related embodiments, including compounds defined by Formula 0, Formula Ia-VII, and Formula Vd/Ve/Vf, together with stereoisomers, isotopic variants, and pharmaceutically acceptable salts. The description includes deuterium-labeled variants with a deuterium isotopic enrichment factor of ≥5, and specifies additional structural variants for the substituent A, including morpholine-diyl, thiazole-diyl, oxazole-diyl, pyrrolidine-diyl, piperidine-diyl, heteroarylene, and phenylene.
The document further describes Ras-binding aziridine-containing macrocyclic compounds and covalent Ras conjugates that bind the Ras Switch-II pocket and form cross-linked conjugates with Ras proteins, including K-Ras, H-Ras, and N-Ras. It also includes treatment-related language, pharmaceutical compositions, prodrug embodiments, and synthetic routes for related intermediates and compounds.
Claims Coverage
The consolidated claim coverage includes one Formula I compound claim with multiple explicit structural limitations, along with additional structure-reference compound claims and pharmaceutical composition claims comprising such compounds and pharmaceutically acceptable excipients. Across the provided claim text, the core inventive features are the parameterized Formula I scaffold and the composition claims built around defined chemical structures.
Formula I compound with morpholine-diyl and fixed ring parameters
A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, wherein A is morpholine-diyl; X1, X2, and X3 are each CH2; m is 1; and n is 1.
Constrained substituent definitions for R1, R2, and R3
R1 is hydrogen, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; R2 is optionally substituted C1-C6 alkyl; and R3 is cyclopentyl.
Specified structure compound claims
A compound of the following structure, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with a specified structure 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 with a specified structure and excipient
A pharmaceutical composition comprising a compound of the following structure and a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on a structurally defined Formula I compound with morpholine-diyl, CH2-defined X1-X3, m = 1, n = 1, and restricted R1, R2, and R3 definitions, together with additional claims directed to specified structures and pharmaceutical compositions containing those compounds with pharmaceutically acceptable excipients.
Stated Advantages
Reduced DUSP6 mRNA up to 48 hours in an in vivo HPAC KRAS G12D xenograft model.
Tumor cross-linking observed in vivo (western blot).
Deep tumor regression and complete regression at the reported oral dosing level in HPAC CDX efficacy/tolerability.
No significant body weight loss at the reported oral dosing level.
Inhibits Ras signaling via steric occlusion.
Creates a new Ras binding pocket through inducing a high-affinity three-component Ras-cyclophilin A (CYPA) complex.
Improved oral bioavailability, represented as %F.
Ras G12D cross-linking performance for compounds in Table 1.
Provides broad chemical scope for deuterated macrocyclic compound structures.
Documented Applications
Use in a covalent KRAS G12D inhibitor context, evaluated in an AsPC-1 pERK potency assay.
In vivo pharmacodynamic evaluation in an HPAC KRAS G12D xenograft model, including measurement of DUSP6 mRNA and assessment of tumor cross-linking.
In vivo efficacy and tolerability assessment in an HPAC CDX xenograft setting, reporting tumor regression, complete regression, and body weight effects after oral dosing.
Methods for treating cancer.
Methods for treating Ras protein-related disorders.
Pharmaceutical compositions and methods of treatment for Ras-mutant cancers.
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