PKM2 modulators and methods for their use
Inventors
Ho, Koc-Kan • Xu, Yong • Saunders, Michael David • Liu, Xiaohui • Pearce, Scott Albert • Wright, Kevin Bret • Foulks, Jason Marc • Parnell, Kenneth Mark • Kanner, Steven Brian • Vollmer, David Lee • Liu, Jihua
Assignees
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Publication Number
US-10766865-B2
Publication Date
2020-09-08
Expiration Date
Abstract
Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Core Innovation
The described invention relates to PKM2 activating compounds and to the use of such compounds to increase PKM2 activity. The modulation is associated with decreased tumorigenicity in a subject in need thereof, and the disclosed compounds include free-base, pharmaceutically acceptable salt, tautomer, prodrug, stereoisomer, isotopically labeled, and metabolic product forms of a defined chemical scaffold.
The disclosed subject matter provides multiple substituted PKM2-activating compound variants sharing a heteroaromatic scaffold, including substituted heterocyclic carboxamides and urea-like scaffold compounds. The structures include extensive substituent variability across ring and side-chain groups, including halogens, phenyl ring hydroxyl and amino groups, cyclobutyl-containing linkers, tertiary amine-like substituents with fluoro/alkoxy modifications, methoxy/ethoxy substituents, and cyclic ethers.
The document further provides pharmaceutical compositions containing the PKM2 activating compounds and their salt, tautomer, and prodrug forms. The therapeutic use case is cancer treatment, including lung cancer and other specified cancer types, and the disclosure includes biochemical characterization of PKM2 activation, structural study of PKM2 with enzyme crystallography and ligand soaking, cell-based assessment, and in vivo xenograft studies supporting decreased tumorigenicity.
Claims Coverage
The claim coverage centers on methods that increase PKM2 activity to achieve decreased tumorigenicity by administering a PKM2 activating compound. The independent claim content is refined by compound form, specific compound variants, cancer context, optional co-administration of chemotherapeutic agents, and specified tumorigenicity settings.
Increasing PKM2 activity to achieve decreased tumorigenicity by administering a PKM2 activating compound
A method for increasing PKM2 activity in the provision of decreased tumorigenicity in a subject in need thereof by administering an effective amount of a PKM2 activating compound.
Administering the PKM2 activating compound as a free-base or pharmaceutically acceptable salt, or tautomer or prodrug
The method administers the PKM2 activating compound in the form of a free-base or a pharmaceutically acceptable salt, or tautomer or prodrug thereof.
Using a specified PKM2 activating compound or its salt, tautomer, or prodrug forms
The administered compound is the provided chemical structure or a pharmaceutically acceptable salt, tautomer, or prodrug of that compound.
Cancer-specific subject context for decreased tumorigenicity
The method is carried out where tumorigenicity is attributed to specified cancers, including lung cancer, pancreatic cancer, skin cancer, colon cancer, breast cancer, kidney cancer, ovarian cancer, hematological malignancy, brain cancer, colorectal cancer, head and neck cancer, prostate cancer, and sarcoma.
Optional co-administration of chemotherapeutic agents
Further administering an effective amount of one or more chemotherapeutic agents to the subject in addition to the PKM2 activating compound.
Overall, the claim coverage centers on a therapeutic method that increases PKM2 activity to produce decreased tumorigenicity via administration of a PKM2 activating compound in specified chemical forms, with refinements for particular cancer types, optional co-treatment with chemotherapeutic agents, and specific compound form variants.
Stated Advantages
Decreased tumorigenicity in a subject.
Increase PKM2 activity in the provision of decreased tumorigenicity.
Provides decreased tumorigenicity in a subject in need thereof while increasing PKM2 activity.
Documented Applications
Therapeutic method for subjects in need thereof to increase PKM2 activity and provide decreased tumorigenicity by administering a PKM2 activating compound.
Cancer treatment, including lung cancer, associated with PKM2 activation.
Cancer treatment in a mammal, including optional activation of PKM2.
Use in subjects with tumorigenicity attributed to lung cancer, pancreatic cancer, skin cancer, colon cancer, breast cancer, kidney cancer, ovarian cancer, and hematological malignancy.
Use with optional co-administration of one or more chemotherapeutic agents.
Cell-based assessment of PKM2 activation and downstream effects, including pyruvate kinase activity and tetramer formation assays.
Testing in cancer cell models and in vivo xenograft studies using an A549-luc-C8 model and related measurements and endpoints.
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