Said Sebti Explained

Said Sebti (Arabic: سيد سبتي, (first name (pronounced as /ar/) is an American cancer researcher who is Professor and Chairman of the Department of Drug Discovery at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fl. Sebti is noted for his work to rehabilitate the 'failed' cancer drug Triciribine, now under development at the pharmaceutical company Prescient Therapeutics (ASX: PTX). Sebti is currently Chief Scientific Officer at Prescient Therapeutics.^[1]

Background

Sebti earned his bachelor's degree in biochemistry from Washington State University in 1980 and his PhD in biochemistry from Purdue University in 1984. From 1985 to 1987 he did post-doctoral work in pharmacology at Yale University. He then spent three years as an assistant professor at the University of Pittsburgh before joining Moffitt Cancer Center in 1996 as Director of its Drug Discovery Program. He was named Professor and Chairman of the Department of Drug Discovery in 2002.^[2]

Research work at the Moffitt Cancer Center

Normal cells often turn cancerous when signal transduction molecules become mutated. Sebti's work at Moffitt has centred on understanding aberrant signal transduction pathways and developing drugs which interfere with such pathways.^[3]

• The Ras superfamily. The Sebti lab has particularly focused on the role of the Ras superfamily, including the Ras and Rho subfamilies and the Ral subfamily.
• Kinases. Sebti's work on the kinase Akt led to his interest in Triciribine. Other kinases that have interested Sebti include Rho-associated kinase^[4] and Aurora kinase.^[5]
• STAT3. In 2003 the Sebti lab discovered JSI-124, a selective STAT3 signaling pathway inhibitor.^[6]
• Bcl/Mcl. The MCL1 member of the Bcl-2 family interests Sebti due to its role in preventing apoptosis. The Sebti lab is working on Mcl-1 inhibitors derived from a natural product called marinopyrrole A.^[7]
• FTase/GGTase. Sebti's work on farnesyltransferase and geranylgeranyltransferase led to the development of the drug now called PTX-100.
• The proteasome. In 2009 the Sebti lab discovered a new proteasome inhibitor called PI-083^[8]

Prescient Therapeutics

Prescient Therapeutics originated in 2014 from two drug discovery programmes pioneered by the Sebti lab, PTX-200 and PTX-100.

• PTX-200. This programme involved the 'rehabilitation' of a previously failed cancer drug called triciribine. This drug, first synthesized in 1971,^[9] was trialled clinically in the 1980s and 1990s but with toxic effects and limited efficacy. However, in the 2000s Sebti and his collaborator Jin Cheng at the University of South Florida established that the drug would be effective against tumours with hyperactivated Akt.^[10]
• PTX-100. This programme involves a compound to block a cancer growth enzyme known as geranylgeranyltransferase type 1 (GGT-I), which plays a role in the inhibition of apoptosis. The compound, originally called GGTI-2418, was invented around 2009 Sebti and Andrew Hamilton, then a Professor of Chemistry at Yale University, now Vice Chancellor at the University of Oxford, invented GGTI.^[11]

Notes and References

1. Web site: Prescient Therapeutics Management Team - Said Sebti. prescienttherapeutics.com. 10 December 2015.
2. Web site: University of South Florida Faculty. Cancerbiology.usf.edu/. 10 December 2015.
3. Web site: Moffitt researchers. Moffitt.org. 10 December 2015.
4. Patel RA . Forinash KD . Pireddu R . Sun Y . Sun N . Martin MP . Schönbrunn E . Lawrence NJ . Sebti SM. . RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. . Cancer Res. . 72 . 19 . 5025–34 . October 1, 2012 . 22846914 . 10.1158/0008-5472.can-12-0954 . 3463757.
5. Yang H . Lawrence HR . Kazi A . Gevariya H . Patel R . Luo Y . Rix U . Schonbrunn E . Lawrence NJ . Sebti SM. . Dual Aurora A and JAK2 kinase blockade effectively suppresses malignant transformation. . Oncotarget . 5 . 10 . 2947–61 . May 30, 2014 . 24930769 . 10.18632/oncotarget.1615 . 4102782.
6. Blaskovich MA . Sun J . Cantor A . Turkson J . Jove R . Sebti SM. . Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice . Cancer Res. . 63 . 6 . 1270–9 . March 15, 2003 . 12649187.
7. Li R . Cheng C . Balasis ME . Liu Y . Garner TP . Daniel KG . Li J . Qin Y . Gavathiotis E . Sebti SM. . Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors. . Eur J Med Chem . 90 . 315–31 . January 27, 2015 . 25437618 . 10.1016/j.ejmech.2014.11.035 . 4445146.
8. Kazi A . Lawrence H . Guida WC . McLaughlin ML . Springett GM . Berndt N . Yip RM . Sebti SM. . Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells. . Cell Cycle . 8 . 12 . 1940–51 . June 15, 2009 . 19471122 . 10.4161/cc.8.12.8798 . 2892826.
9. Schram KH . Townsend LB . 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 |journal=Tetrahedron Lett. |volume=12 |issue=49 |pages=4757–4760 |date=December 3, 1971 |pmid= |doi= 10.1016/s0040-4039(01)87546-8 ].
10. Yang L . Dan HC . Sun M . Liu Q . Sun XM . Feldman RI . Hamilton AD . Polokoff M . Nicosia SV . Herlyn M . Sebti SM . Cheng JQ. . 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 . July 1, 2004 . 10.1158/0008-5472.can-04-0343 . 15231645. free .
11. WO . 2010088457 . application . Methods for inducing tumor regression, inhibiting tumor growth, and inducing apoptosis in breast tumors with geranylgeranyltransferase I inhibitors . 2010-08-05 . 2010-01-29 . 2009-01-29 . Said Sebti . Andrew Hamilton . H. Lee Moffitt Cancer Center & Research Institute . Yale University.