Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension
Vinny Negi, Jimin Yang, Gil Speyer, Andrés Pulgarin, Adam Handen, Jingsi Zhao, Yi‐Yin Tai, Ying Tang, Miranda K. Culley, Qiujun Yu, Patricia A. Forsythe, Anastasia Gorelova, Annie Watson, Yassmin Al Aaraj, Taijyu Satoh, Maryam Sharifi‐Sanjani, Arun Rajaratnam, John Sembrat, Steeve Provencher, Xianglin Yin, Sara O. Vargas, Mauricio Rojas, Sébastien Bonnet, Stéphanie Torrino, Bridget K. Wagner, Stuart L. Schreiber, Mingji Dai, Thomas Bertero, Imad Al Ghouleh, Seungchan Kim, Stephen Y. Chan
Abstract
Cancer therapies are being considered for treating rare noncancerous diseases like pulmonary hypertension (PH), but effective computational screening is lacking. Via transcriptomic differential dependency analyses leveraging parallels between cancer and PH, we mapped a landscape of cancer drug functions dependent upon rewiring of PH gene clusters. Bromodomain and extra-terminal motif (BET) protein inhibitors were predicted to rely upon several gene clusters inclusive of galectin-8 (LGALS8). Correspondingly, LGALS8 was found to mediate the BET inhibitor–dependent control of endothelial apoptosis, an essential role for PH in vivo. Separately, a piperlongumine analog’s actions were predicted to depend upon the iron-sulfur biogenesis gene ISCU. Correspondingly, the analog was found to inhibit ISCU glutathionylation, rescuing oxidative metabolism, decreasing endothelial apoptosis, and improving PH. Thus, we identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for PH. These results establish a wide-ranging, network dependency platform to redefine cancer drugs for use in noncancerous conditions.