Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

Area of Science:

• Genomics
• Pharmacology
• Translational Medicine

Background:

• Pulmonary hypertension (PH) is a rare disease lacking effective computational screening for drug discovery.
• Cancer therapies show potential for treating noncancerous diseases like PH, but require robust screening methods.

Purpose of the Study:

• To develop a computational screening platform for repurposing cancer drugs for PH.
• To identify specific drug-gene interactions crucial for treating PH.

Main Methods:

• Transcriptomic differential dependency analyses were used to map cancer drug functions in PH gene clusters.
• Key drug-gene axes, including BET inhibitors targeting galectin-8 (LGALS8) and a piperlongumine analog targeting ISCU, were identified and validated.

Main Results:

• LGALS8 was identified as mediating BET inhibitor-dependent control of endothelial apoptosis in PH.
• A piperlongumine analog was found to inhibit ISCU glutathionylation, improving oxidative metabolism and reducing endothelial apoptosis in PH.
• The study identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for PH.

Conclusions:

• A network dependency platform was established to redefine cancer drugs for noncancerous conditions like PH.
• The findings highlight specific therapeutic targets and drug candidates for PH treatment.
• This approach offers a broad strategy for repurposing existing drugs for rare diseases.