A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy
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Author(s)
Awuah, Samuel
Zheng, Yaorong
Bruno, Peter Michael
Hemann, Michael
Lippard, Stephen J.
Date Issued
November 2015
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Awuah, Samuel G. et al. “A Pt(IV) Pro-Drug Preferentially Targets Indoleamine-2,3-Dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy.” Journal of the American Chemical Society 137.47 (2015): 14854–14857.
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Author's final manuscript
Abstract
Expression of indoleamine-2,3-dioxygenase (IDO), an immunosuppressive enzyme in human tumors, leads to immune evasion and tumor tolerance. IDO is therefore a tumor immunotherapeutic target, and several IDO inhibitors are currently undergoing clinical trials. IDO inhibitors can enhance the efficacy of common cancer chemotherapeutics. Here we investigated
Pt(IV) – (D)-1-methyltryptophan conjugates 1 and 2 for combined immunomodulation and DNA cross-link-triggered apoptosis for cancer ‘immuno-chemotherapy’. Compound 2 effectively kills hormone-dependent, cisplatin-resistant human ovarian cancer cells, inhibiting IDO by
transcriptional deregulation of the auto-crine-signaling loop IDO-AHR-IL6, which blocks kynurenine production and promotes T-cell proliferation. Additionally, 1 and 2 display low toxicity in mice and are stable in blood. To our knowledge, this construct is the first Pt drug candidate with immune checkpoint blockade properties.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1021/jacs.5b10182
