Therapeutic small molecules for treatment of pulmonary hypertension
Inventors
CHAN, Stephen Yu-Wah • Kim, Seungchan
Assignees
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Publication Number
US-12599592-B2
Publication Date
2026-04-14
Expiration Date
Abstract
Disclosed are pathogenic mechanisms in pulmonary hypertension and molecular inhibitors of the same. Particularly, GSTP1 (glutathione S-transferase P1) have been demonstrated as having a role in regulating the endothelial ISCU function in pulmonary hypertension. Accordingly, methods for treating pulmonary hypertension in a subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition that inhibits glutathione S-transferase P (GSTP1) and/or increasing ISCU expression are disclosed. The GSTP1 inhibitor can comprise a piperlongumine analog, such as BRD-K34222889, or a derivative thereof.
Core Innovation
The invention relates to therapeutic approaches for pulmonary hypertension by administering a therapeutically effective amount of a pharmaceutical composition comprising piperlongumine analog BRD-K34222889 or a derivative thereof. The piperlongumine analog has a structure according to Formula I, with defined substituent variables, and covers pharmaceutically acceptable salts, esters, or prodrugs.
The disclosure targets the GSTP1-ISCU axis and regulation of ISCU S-glutathionylation, which affects ISCU stability or expression and endothelial metabolic function. GSTP1 inhibition is described as increasing ISCU protein stability by preventing glutathionylation and restoring oxidative metabolism, while reducing pulmonary arterial endothelial cell apoptosis and improving pulmonary arterial hypertension.
The described approach is also associated with endothelial dysfunction, including regulation of a PH gene cluster centered on galectin-8 (LGALS8), and with drug-gene-cluster dependency rewiring. The disclosure further describes broader drug repurposing across pulmonary hypertension subtypes and endothelial pathobiology, including pulmonary arterial hypertension and related ISCU-instability disorders.
Claims Coverage
The claim coverage provides one independent method claim and dependent refinements. It centers on treating pulmonary hypertension with BRD-K34222889 or a derivative having a defined Formula I structure, and includes 5 inventive features across the claims content provided.
Treating pulmonary hypertension with a Formula I piperlongumine analog
A method of treating pulmonary hypertension in a subject in need thereof by administering a therapeutically effective amount of a pharmaceutical composition comprising piperlongumine analog BRD-K34222889 or a derivative thereof, wherein the piperlongumine analog BRD-K34222889 or a derivative thereof has a structure according to Formula I with defined substituent parameters and pharmaceutically acceptable salt, ester, or prodrug forms.
Pulmonary arterial hypertension treatment
The pulmonary hypertension is pulmonary arterial hypertension.
Reducing pulmonary arterial endothelial cell apoptosis
The pharmaceutical composition inhibits or reduces pulmonary arterial endothelial cell apoptosis in a subject in need thereof.
Specific Formula I selection for A1 and A2
In the Formula I structure, A1 equals C(O) and A2 equals —C≡C—.
Specific Formula I selection for X
In the Formula I structure, X equals CH2.
Overall, the claims coverage centers on administration of a BRD-K34222889 pharmaceutical composition having a defined Formula I structure, with dependent claims narrowing to pulmonary arterial hypertension, reduction of pulmonary arterial endothelial cell apoptosis, and specific selections for Formula I variables including A1, A2, and X.
Stated Advantages
Increases ISCU protein stability by preventing glutathionylation.
Restores oxidative metabolism.
Reduces pulmonary arterial endothelial cell apoptosis.
Improves pulmonary arterial hypertension.
Documented Applications
Therapeutic treatment of pulmonary hypertension, including pulmonary arterial hypertension, in a subject in need thereof.
Treatment of related ISCU-instability disorders.
Diagnostic and efficacy-assay concepts based on detecting GSTP1 expression and GSTP1 inhibition in samples.
Optional combination therapy for pulmonary hypertension using conventional pulmonary hypertension agent classes.
Use in endothelial dysfunction contexts associated with apoptosis reduction under hypoxia and inflammatory conditions.
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