Senolytic compositions and uses thereof

Inventors

Gallop, Mark A. • Klein, Julian • Quarta, Marco

Assignees

Rubedo Life Sciences Inc

Abstract

Provided herein are senolytic agents for selectively killing senescent cells that are associated with numerous pathologies and diseases, including age-related pathologies and diseases. As disclosed herein, senescent cell-associated diseases and disorders may be treated or prevented by administering at least one senolytic agent or pharmaceutical compositions thereof. The senescent cell-associated diseases or disorders treated or prevented by the methods described herein include, but are not limited to, cardiovascular diseases or disorders, cardiovascular diseases and disorders associated with arteriosclerosis, such as atherosclerosis, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), osteoarthritis, inflammatory diseases or disorders, autoimmune diseases or disorders, pulmonary diseases or disorders, neurological diseases or disorders, dermatological diseases or disorders, chemotherapeutic side effects, radiotherapy side effects, metastasis and metabolic diseases.

Core Innovation

The disclosure relates to senolytic compositions and uses that rely on non-toxic prodrugs of senolytic agents and senolytic agents as prodrugs and conjugates, including apoptosis-promoting agents, duocarmycin or related cytotoxins, pyrrolo[2,1-c][1,4]benzodiazepines, Akt inhibitors, and the proteasome inhibitor delanzomib. The prodrugs are activated by intracellular hydrolases, including glycosidases, and include glycosidic promoieties, O-glycoside conjugates, O-galactoside and O-fucoside conjugates, and sugar prodrugs such as 5-fluorouridine-5′-O-β-D-galactopyranoside and 5-fluorouridine-5′-O-α-L-fucopyranoside.

The disclosure emphasizes that intracellular hydrolases such as glycosidases or senescence-associated β-galactosidase and α-fucosidase preferentially activate the prodrugs in senescent cells to release the toxic parent compound or 5-fluorouridine. It also describes prodrug-like conjugates defined by formulae and lysosome-activated prodrugs based on glycosidase hydrolysis, together with hydroxamic acid masking of a hydroxamic acid zinc-chelating moiety, protected and deprotected tetrahydropyran derivatives, and HCl salt forms.

The document frames a problem of selectivity and toxicity by describing known senolytic mechanisms and their limitations, and by stating a rationale to improve selectivity and reduce toxicity to non-senescent cells. It includes disease- and tissue-specific contexts for senolytic treatment or prevention across cardiovascular, pulmonary, neurological, dermatological, metabolic, inflammatory, autoimmune, fibrotic, ophthalmic, and osteoarthritic settings.

Claims Coverage

The independent claims are directed to structurally defined compounds, including pharmaceutically acceptable salts, hydrates, or solvates, and to methods of treating a senescence-associated disease or disorder by administering a therapeutically effective amount to a subject. Across the independent claim families, the main inventive features focus on the specific compound structure, the pharmaceutical composition context with a pharmaceutically acceptable excipient, and therapeutic administration for senescence-associated disease treatment.

Overall, the claim coverage is directed to structurally defined compounds, including salts, hydrates, and solvates, together with pharmaceutical compositions containing a pharmaceutically acceptable excipient and methods for treating a senescence-associated disease or disorder by administering therapeutically effective amounts of the compound or the composition.

Stated Advantages

Documented Applications