A Pt(IV) Pro-drug Preferentially Targets Indoleamine-2,3-dioxygenase, Providing Enhanced Ovarian Cancer Immuno-Chemotherapy

J Am Chem Soc. 2015 Dec 2;137(47):14854-7. doi: 10.1021/jacs.5b10182. Epub 2015 Nov 18.

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 investigate 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 autocrine-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Female
  • Humans
  • Immunotherapy*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / therapy*

Substances

  • Antineoplastic Agents
  • Indoleamine-Pyrrole 2,3,-Dioxygenase