Drug Analogues Are Potent Inhibitors of Cancer-related Stat3

A library of analogues of the Stat3 inhibitor S3I-201 was prepared and found to be substantially more potent than S3I-201 both in vitro and in studies carried out on cancer cell cultures.

Stat3 is a member of the Stat protein family. In response to cytokines and growth factors, Stat family members are phosphorylated by the receptor-associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. Stat3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Stat3 is essential for the differentiation of TH17 helper T cells, which has been implicated in a variety of autoimmune diseases. Constitutive Stat3 activation is associated with various human cancers and commonly suggests poor prognosis. It has antiapoptotic as well as proliferative effects.

The drug S3I-201 inhibits growth and induces apoptosis preferentially in tumor cells that contain persistently activated Stat3. The current work was undertaken by investigators at the University of Toronto, Mississauga (ON, Canada) to increase both the potency and metabolic stability of S3I-201. They reported in the July 30, 2009, online edition of the journal ChemBioChem: A European Journal of Chemical Biology that two of a series of analogues, the drugs SF-1-066 and SF-1-121, showed impressive in vitro and whole-cell anti-Stat3 activities.

"These are some of the most potent inhibitors in the literature so far for this particular protein,” said senior author Dr. Patrick Gunning, professor of chemical and physical sciences at the University of Toronto Mississauga. "In some cases, they were more than twice as effective as the existing inhibitor.”

"The molecules we have created are particularly nice because they are showing selectivity against cancer cells but not against healthy cells,” said Dr. Gunning. "This molecule could be used in conjunction with typical chemotherapeutics, and it could mean that drugs will have less resistance, so you could use lower dosages and cause fewer side effects.”

Related Links:
University of Toronto, Mississauga