2. Academic Validation
  3. Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension

  • Sci Adv. 2021 Oct 22;7(43):eabh3794. doi: 10.1126/sciadv.abh3794.
Vinny Negi 1,  Jimin Yang 1,  Gil Speyer 2,  Andres Pulgarin 1,  Adam Handen 1,  Jingsi Zhao 1,  Yi Yin Tai 1,  Ying Tang 1,  Miranda K Culley 1,  Qiujun Yu 1,  Patricia Forsythe 1,  Anastasia Gorelova 1,  Annie M Watson 1,  Yassmin Al Aaraj 1,  Taijyu Satoh 1 3,  Maryam Sharifi-Sanjani 1,  Arun Rajaratnam 1,  John Sembrat 4,  Steeve Provencher 5,  Xianglin Yin 6,  Sara O Vargas 7,  Mauricio Rojas 8,  Sébastien Bonnet 5,  Stephanie Torrino 9,  Bridget K Wagner 10,  Stuart L Schreiber 10,  Mingji Dai 6,  Thomas Bertero 9,  Imad Al Ghouleh 1,  Seungchan Kim 11,  Stephen Y Chan 1
Affiliations

Affiliations

  • 1 Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 2 Research Computing, Arizona State University, Tempe, AZ, USA.
  • 3 Department of Cardiovascular Medicine, Tohoku University of Graduate School of Medicine, 1-1 Seiryomachi, Aoba-ku, 980-8574 Sendai, Japan.
  • 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 5 Pulmonary Hypertension and Vascular Biology Research Group, Faculty of Medicine, Laval University, Quebec, QC, Canada.
  • 6 Department of Chemistry, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN, USA.
  • 7 Department of Pathology, Boston Children's Hospital, MA, USA.
  • 8 Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Ohio State University College of Medicine, Columbus, OH, USA.
  • 9 Université Côte d'Azur, CNRS, IPMC, Sophia-Antipolis, France.
  • 10 Department of Chemistry and Chemical Biology, Harvard University; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 11 Prairie View A&M Univ, Prairie View, TX, USA.
PMID: 34669463 DOI: 10.1126/sciadv.abh3794
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.

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