Gene expression–based discovery of atovaquone as a STAT3 inhibitor and anticancer agent

Michael Xiang, Haesook Kim, Vincent T. Ho, Sarah R. Walker, Michal Bar-Natan, Melodi Anahtar, Suhu Liu, Patricia A. Toniolo, Yasmin Kroll, Nichole Jones, Zachary T. Giaccone, Lisa N. Heppler, Darwin Q. Ye, Jason J. Marineau, Daniel Shaw, James E. Bradner, Traci Blonquist, Donna Neuberg, Claudio Hetz, Richard M. Stone, Robert J. Soiffer and David A. Frank

Key Points

  • The FDA-approved drug atovaquone is a novel, clinically available inhibitor of STAT3 at standard human plasma concentrations.

  • Atovaquone shows anticancer efficacy in vitro, in vivo, and in a retrospective study of AML patient outcomes after atovaquone treatment.


The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans.

  • Submitted July 24, 2015.
  • Accepted August 1, 2016.
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