Triciribine

Triciribine
Identifiers
CAS Number 35943-35-2
ChemSpider 58865
Chemical and physical data
Formula C13H16N6O4
Molar mass 320.12 g/mol
3D model (Jmol) Interactive image

Triciribine is a cancer drug which was first synthesised in the 1970s and trialled clinically in the 1980s and 1990s without success. Following the discovery in the early 2000s that the drug would be effective against tumours with hyperactivated Akt, it is now again under consideration in a variety of cancers. As PTX-200, the drug is currently in two early stage clinical trials in breast cancer and ovarian cancer being conducted by the small molecule drug development company Prescient Therapeutics.

Background

Triciribine is a cell-permeable tricyclic nucleoside that inhibits the phosphorylation, activation, and signalling of all three family members of Akt - Akt-1, Akt-2 and Akt-3. These are serine/threonine protein kinases in the phosphoinositide 3-kinase (PI3K) signalling pathway that play a critical role in the regulation of cell proliferation and survival. Following recruitment of Akt to the plasma membrane, phosphorylation at threonine 308 and serine 473 (Akt-1 numbering) by PDK-1 or PDK-2 results in full activation of the enzyme. Triciribine does not inhibit PI3K or PDK1, the direct upstream activators of Akt, nor does it inhibit PKC, PKA, ERK1/2, serum- and glucocorticoid-inducible kinase, p38, STAT3, or JNK signalling pathways.[1]

Early development, 1971-2004

Triciribine, first synthesized in 1971,[2] was found to have definite anti-cancer properties[3] and a phosphate ester of the drug went into clinical trials in the 1980s because it had improved solubility. The trials found the drug to be toxic with limited efficacy. For example, a Phase I study in 1984 evaluating 33 advanced cancer patients using a five-day continuous infusion schedule found hyperglycemia, hepatotoxicity, and thrombocytopenia as common toxicities with only one patient's cancer improving.[4] A Phase II trial in 1993 found only two responders out of 21 cervical cancer patients.[5] Triciribine was widely considered to be a failed cancer drug until its 'rehabilitation' in the early 2000s.

Development as an Akt inhibitor, 2004 -

In the early 2000s Said Sebti at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fl and Jin Cheng at the University of South Florida established that Triciribine would be effective against tumours with hyperactivated AKT.[6] By 2010 important parts of the mechanism of action for Triciribine had been elucidated, including its preventing AKT membrane translocation,[7] and specifically its binding to the PH domain of AKT, thereby blocking its recruitment to the membrane, leading to subsequent inhibition of AKT phosphorylation.[8]

Current development

As PTX-200 Triciribine is currently in a Phase Ib/II study in breast cancer (ClinicalTrials.gov identifier NCT01697293[14]) and a Phase Ib trial in platinum resistant ovarian cancer (ClinicalTrials.gov identifier NCT01690468[15]).

References

  1. ↑ Yang L; Dan HC; Sun M; Liu Q; Sun XM; Feldman RI; Hamilton AD; Polokoff M; Nicosia SV; Herlyn M; Sebti SM; Cheng JQ. (July 1, 2004). "Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt.". Cancer Res. 64 (13): 4394–9. doi:10.1158/0008-5472.can-04-0343. PMID 15231645.
  2. ↑ Schram KH, Townsend LB (December 3, 1971). "The synthesis of 6-amino-4-methyl-8-(β-D-ribofuranosyl (4-H)pyrrolo-[4-3-2depyrimido(4, 5-C) pyridazine, a new tricyclic nucleoside". Tetrahedron Lett. 12 (49): 4757–4760. doi:10.1016/s0040-4039(01)87546-8.
  3. ↑ Townsend LB; Milne GH. (August 8, 1975). "Synthesis, chemical reactivity, and chemotherapeutic activity of certain selenonucleosides and nucleosides related to the pyrrolo(2,3-d)pyrimidine nucleoside antibiotics.". Ann N Y Acad Sci. 22: 91–103. PMID 1059377.
  4. ↑ Feun LG; Savaraj N; Bodey GP; Lu K; Yap BS; Ajani JA; Burgess MA; Benjamin RS; McKelvey E; Krakoff I. (August 1, 2004). "Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule.". Cancer Res. 44 (8): 3608–12. PMID 6744283.
  5. ↑ Feun LG1, Blessing JA, Barrett RJ, Hanjani P. (December 1, 1993). "A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study.". Am J Clin Oncol. 16 (6): 506–8. doi:10.1097/00000421-199312000-00010. PMID 8256767.
  6. ↑ Yang L; Dan HC; Sun M; Liu Q; Sun XM; Feldman RI; Hamilton AD; Polokoff M; Nicosia SV; Herlyn M; Sebti SM; Cheng JQ. (July 1, 2004). "Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt.". Cancer Res. 64 (13): 4394–9. doi:10.1158/0008-5472.can-04-0343. PMID 15231645.
  7. ↑ Kim D; Sun M; He L; Zhou QH; Chen J; Sun XM; Bepler G; Sebti SM; Cheng JQ. (March 12, 2010). "A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation.". J Biol Chem. 285 (11): 8383–94. doi:10.1074/jbc.M109.094060. PMC 2832988Freely accessible. PMID 20068047.
  8. ↑ Berndt N; Yang H; Trinczek B; Betzi S; Zhang Z; Wu B; Lawrence NJ; Pellecchia M; Schönbrunn E; Cheng JQ; Sebti SM. (November 1, 2010). "The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane.". Cell Death Differ. 11: 1795–804. doi:10.1038/cdd.2010.63. PMC 2952662Freely accessible. PMID 20489726.
  9. ↑ Balasis ME; Forinash KD; Chen YA; Fulp WJ; Coppola D; Hamilton AD; Cheng JQ; Sebti SM. (May 1, 2011). "Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice.". Clin Cancer Res. 17 (9): 2852–62. doi:10.1158/1078-0432.CCR-10-2544. PMC 3156694Freely accessible. PMID 21536547.
  10. ↑ Kim R; Yamauchi T; Husain K; Sebti S; Malafa M. (September 1, 2015). "Triciribine Phosphate Monohydrate, an AKT Inhibitor, Enhances Gemcitabine Activity in Pancreatic Cancer Cells". Anticancer Res. 35 (9): 4599–604. PMID 26254348.
  11. ↑ Garrett CR; Coppola D; Wenham RM; Cubitt CL; Neuger AM; Frost TJ; Lush RM; Sullivan DM; Cheng JQ; Sebti SM. (December 1, 2011). "Phase I pharmacokinetic and pharmacodynamic study of triciribine phosphate monohydrate, a small-molecule inhibitor of AKT phosphorylation, in adult subjects with solid tumors containing activated AKT". Invest New Drugs. 29 (6): 1381–9. doi:10.1007/s10637-010-9479-2. PMC 4612514Freely accessible. PMID 20644979.
  12. ↑ "Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) in Adult Patients With Advanced Hematologic Malignancies". Clinicaltrials.gov. U.S. National Institutes of Health. Retrieved 7 December 2015.
  13. ↑ Sampath D; Malik A; Plunkett W; Nowak B; Williams B; Burton M; Verstovsek S; Faderl S; Garcia-Manero G; List AF; Sebti S; Kantarjian HM; Ravandi F; Lancet JE. (November 1, 2013). "Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies.". Leuk Res. 37 (11): 1461–7. doi:10.1016/j.leukres.2013.07.034. PMC 4205589Freely accessible. PMID 23993427.
  14. ↑ "riciribine Phosphate, Paclitaxel, Doxorubicin Hydrochloride, and Cyclophosphamide in Treating Patients With Stage IIB-IV Breast Cancer". Clinicaltrials.gov. U.S. National Institutes of Health. Retrieved 7 December 2015.
  15. ↑ "Triciribine and Carboplatin in Ovarian Cancer". Clinicaltrials.gov. U.S. National Institutes of Health.
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