Triciribine is a cancer drug which was first synthesized in the 1970s and studied 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.
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| Formula | C13H16N6O4 |
| Molar mass | 320.309 g·mol−1 |
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Background
editTriciribine is a cell-permeable unnatural nucleoside that inhibits the phosphorylation 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
editTriciribine, 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.[citation needed]
Development as an Akt inhibitor, 2004 -
editIn 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, specifically its binding to the PH domain of AKT, thereby blocking its recruitment to the membrane, leading to subsequent inhibition of AKT phosphorylation.[7]
- Pre-clinical work, 2004-2015. A number of pre-clinical studies confirmed the initial 2004 finding, including one showing synergy with tipifarnib[8] and one showing effectiveness in pancreatic cancer cells.[9]
- Phase I in solid tumors, 2011. This pharmacokinetic and pharmacodynamic study suggested that treatment with PTX-200 could inhibit phosphorylated AKT in tumours at doses that were tolerable.[10]
- Phase I in advanced leukemia, 2013 (ClinicalTrials.gov identifier NCT00642031[11]). This study, conducted at the Lee Moffitt as well as the M.D. Anderson Cancer Center, tested Triciribine as a single agent. Of the 32 evaluable patients, 15 had progressive disease and 17 had stable disease following a single cycle of treatment. Of the patients with stable disease, 3 patients with AML achieved ≥50% bone marrow blast reduction and a fourth patient with chronic myelomonocytic leukemia had marked spleen reduction and resolution of leukocytosis.[12]
Current development
editAs PTX-200, triciribine is currently in a Phase Ib/II study in breast cancer[13]) and a Phase Ib trial in platinum resistant ovarian cancer.[14] These trials completed in 2020 and 2019 respectively without publishing data, suggesting negative results.
References
edit- ^ Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, et al. (July 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 Research. 64 (13): 4394–4399. doi:10.1158/0008-5472.can-04-0343. PMID 15231645. S2CID 1068659.
- ^ 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.
- ^ Townsend LB, Milne GH (August 1975). "Synthesis, chemical reactivity, and chemotherapeutic activity of certain selenonucleosides and nucleosides related to the pyrrolo(2,3-d)pyrimidine nucleoside antibiotics". Annals of the New York Academy of Sciences. 255 (1): 91–103. Bibcode:1975NYASA.255...91T. doi:10.1111/j.1749-6632.1975.tb29216.x. PMID 1059377. S2CID 42481985.
- ^ Feun LG, Savaraj N, Bodey GP, Lu K, Yap BS, Ajani JA, et al. (August 1984). "Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule". Cancer Research. 44 (8): 3608–3612. PMID 6744283.
- ^ Feun LG, Blessing JA, Barrett RJ, Hanjani P (December 1993). "A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group Study". American Journal of Clinical Oncology. 16 (6): 506–508. doi:10.1097/00000421-199312000-00010. PMID 8256767. S2CID 2182546.
- ^ Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, et al. (July 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 Research. 64 (13): 4394–4399. doi:10.1158/0008-5472.can-04-0343. PMID 15231645. S2CID 1068659.
- ^ Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, et al. (November 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 and Differentiation. 17 (11): 1795–1804. doi:10.1038/cdd.2010.63. PMC 2952662. PMID 20489726.
- ^ Balasis ME, Forinash KD, Chen YA, Fulp WJ, Coppola D, Hamilton AD, et al. (May 2011). "Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice". Clinical Cancer Research. 17 (9): 2852–2862. doi:10.1158/1078-0432.CCR-10-2544. PMC 3156694. PMID 21536547.
- ^ Kim R, Yamauchi T, Husain K, Sebti S, Malafa M (September 2015). "Triciribine Phosphate Monohydrate, an AKT Inhibitor, Enhances Gemcitabine Activity in Pancreatic Cancer Cells". Anticancer Research. 35 (9): 4599–4604. PMID 26254348.
- ^ Garrett CR, Coppola D, Wenham RM, Cubitt CL, Neuger AM, Frost TJ, et al. (December 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". Investigational New Drugs. 29 (6): 1381–1389. doi:10.1007/s10637-010-9479-2. PMC 4612514. PMID 20644979.
- ^ Clinical trial number NCT00642031 for "Triciribine Phosphate Monohydrate (TCN-PM, VD-0002) in Adult Patients With Advanced Hematologic Malignancies" at ClinicalTrials.gov
- ^ Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, et al. (November 2013). "Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies". Leukemia Research. 37 (11): 1461–1467. doi:10.1016/j.leukres.2013.07.034. PMC 4205589. PMID 23993427.
- ^ Clinical trial number NCT01697293 for "Riciribine Phosphate, Paclitaxel, Doxorubicin Hydrochloride, and Cyclophosphamide in Treating Patients With Stage IIB-IV Breast Cancer" at ClinicalTrials.gov
- ^ Clinical trial number NCT01690468 for "Triciribine and Carboplatin in Ovarian Cancer" at ClinicalTrials.gov