Compositions and methods for treating cancer
Inventors
Ostrem, Jonathan • Peters, Ulf • Shokat, Kevan M.
Assignees
University of California San Diego UCSD
Publication Number
US-12365693-B2
Publication Date
2025-07-22
Expiration Date
2033-04-10
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Abstract
K-Ras is the most frequently mutated oncogene in human cancer. Disclosed herein are compositions and methods for modulating K-Ras and treating cancer.
Core Innovation
The invention provides compositions and methods for modulating K-Ras protein, including chemically tractable oncogenic mutants such as K-RasG12C, to treat cancer. The compounds described include a particular formula incorporating a Switch 2—Binding Pocket binding moiety, linkers, and an electrophilic chemical moiety capable of forming covalent bonds with K-Ras cysteine or aspartate residues. These compounds selectively bind mutant K-Ras proteins and alter their function by forming covalent bonds and modulating critical regions such as Switch 2.
The problem addressed is the difficulty in directly targeting Ras proteins, particularly K-Ras, which is the most frequently mutated oncogene in human cancer. Prior attempts to target Ras with reversible inhibitors have been largely unsuccessful. The invention solves this by using covalent chemistry to target an allele-specific pocket on mutant forms of K-Ras, thereby modulating its activity and offering new therapeutic avenues for treating cancer associated with mutant K-Ras.
Claims Coverage
The patent includes multiple independent claims focusing on a human K-Ras protein covalently bonded to a compound of a defined formula and methods of using such compounds.
Human K-Ras protein covalently bonded to a compound
A human K-Ras protein having a cysteine at residue 12 covalently bonded to a compound of formula R1-L1-L2-L3-E, where R1 is a Switch 2—Binding Pocket binding moiety, L1-L3 are linkers, and E is an electrophilic moiety capable of forming a covalent bond with cysteine or aspartate residues in K-Ras.
Specific substitution patterns on the Switch 2-binding moiety
R1 is selected from substituted monocyclic heteroaryl or substituted fused ring (6,5 or 6,6) heteroaryl groups. Substituents on R1 are independently selected from a defined set including halogen, oxo, trifluoromethyl, cyano, hydroxyl, amino, carboxyl, and other groups, allowing for chemical diversity and optimization.
Methods for identifying covalent inhibitors
Methods involving providing structural models of reference compounds bound to the Switch 2 binding pocket of K-Ras, identifying amino acid residues (cysteine, aspartate, lysine, tyrosine, glutamate) near the pocket, modeling test compounds with electrophilic moieties, and selecting those with suitable proximity to form covalent bonds.
Modulation of K-Ras activity and selective binding
Compounds selectively bind mutant K-Ras forms (e.g., G12C, G12D, G13C, G13D), forming covalent bonds and modulating K-Ras activities such as GTPase activity, nucleotide exchange, effector protein binding, and post-translational modifications. The compounds bind behind Switch II and distort Switch I and II conformations, affecting downstream signaling.
The claims cover mutant-specific covalent binding of compounds to K-Ras at residue 12 cysteine, defined chemical moieties and substitutions enabling selective interaction with a unique Switch 2 binding pocket, methods to identify these covalent inhibitors, and therapeutic methods for treating mutant K-Ras associated cancers by modulating K-Ras activity.
Stated Advantages
Provides selective small molecules that target oncogenic mutant K-Ras (e.g. K-Ras G12C) without binding to the wild-type protein.
Identifies a novel druggable pocket (Switch 2—Binding Pocket) for K-Ras, previously not apparent, enabling new avenues for direct pharmacological inhibition.
Compounds bind covalently and induce conformational changes in Switch 1 and Switch 2 regions, essential for downstream signaling, effectively blocking Ras activation pathways.
Demonstrates capability of inhibiting the proliferation of K-Ras mutant-driven cancer cells under nutrient-deficient or serum deprivation conditions, indicating therapeutic potential.
Documented Applications
Treating cancer by administering compounds that modulate or inhibit mutant K-Ras proteins.
Therapeutic use in cancers associated with aberrant or mutant K-Ras, including lung cancer, non-small cell lung cancer, colon cancer, colorectal cancer, pancreatic cancer, breast cancer, and leukemia.
Diagnostic methods to identify patients bearing mutant K-Ras in malignant or neoplastic cells, with subsequent administration of K-Ras modulating compounds.
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