Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

M. Espona-Fiedler, V. Soto-Cerrato, A. Hosseini, J. M. Lizcano, V. Guallar, R. Quesada, T. Gao, R. Pérez-Tomás

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.

Original languageEnglish
Pages (from-to)489-496
Number of pages8
JournalBiochemical Pharmacology
Issue number4
StatePublished - Feb 15 2012

Bibliographical note

Funding Information:
The authors thank Marta Taulés for technical assistance from Centres Científics i Tecnològics (Universitat de Barcelona) and Robin Rycroft for language assistance. This work was supported by a research grant from Spanish government and the European Union (FIS-PI10/00338).


  • Melanoma
  • Obatoclax
  • PI3K/AKT
  • Prodigiosin
  • mTOR complexes
  • mTOR inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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