US 2026/0097022 A1 · COMPOUNDS AND USES THEREOF

Abstract

The accumulation of senescent cells is associated with aging, inflammation, and cellular dysfunction. Senolytic drugs can alleviate age-related comorbidities by selectively killing senescent cells. Described herein is a screen of 2,352 compounds for senolytic activity in a model of senescence and trained neural networks to predict the senolytic activities of >800,000 molecules. Methods, systems, and algorithms of the disclosure can enrich for structurally diverse compounds with senolytic activity. Compounds of the disclosure can comprise drug-like compounds which selectively target senescent cells across different senescence models, with more favorable medicinal chemistry properties than, and selectivity comparable to, those of a documented senolytics. Molecular docking simulations of compound binding to several senolytic protein targets, combined with time-resolved fluorescence energy transfer experiments, indicate that these compounds act in part by inhibiting Bcl-2, a regulator of cellular apoptosis. Compounds of the present disclosure can decrease senescent cell burden and mRNA expression of senescence-associated genes.

Claims21

Dependent claims

1-25. (canceled)

A method of treating a senescence-associated disease or disorder or an age-related disease or disorder in a subject comprising, administering to the subject a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein;
R1 and R4 are each independently selected from hydrogen and C1-6 alkyl;
each R2 and R3 is independently selected from halogen, —OR5, SR5, —N(R5)2, —C(O)R6, —C(O)N(R5)2, —N(R5)C(O)R6, —C(O)OR5, —OC(O)R6, —S(O)2R6, —S(O)2N(R5)2, —NO2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
wherein each C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally substituted with one or more substituents independently selected from halogen, —OR5, —SR5, —N(R5)2, —C(O)R6, —C(O)N(R5)2, —N(R5)C(O)R6, —C(O)OR5, —OC(O)R6, —NO2, ═O, and —CN;
each R5 is independently selected from:
hydrogen;
and C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —NH2—NO2, —O, and —CN;
each R6 is independently selected from:
C1-6 alkyl optionally substituted with one more substituents independently selected from halogen, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —NH2—NO2, ═O, and —CN;
m is 0, 1, 2, 3, 4, or 5;
and
n is 0, 1, 2, 3, 4, or 5.

9 more elements

Dependencies are inferred from the claim text.

Compounds and uses thereof

Life of this patent

Compounds and uses thereof

Life of this patent

Abstract

Claims21