The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.
Ovarian cancer is the most lethal gynecological malignancy affecting American women. Current hypotheses concerning the etiology of ovarian cancer propose that a reduction in the lifetime number of ovulations decreases ovarian cancer risk. Advanced serous carcinoma shares several biomarkers with fallopian tube epithelial cells, suggesting that some forms of ovarian carcinoma may originate in the fallopian tube. Currently, the impact of ovulation on the tubal epithelium is unknown. In CD1 mice, ovulation did not increase tubal epithelial cell proliferation as measured by bromodeoxyuridine incorporation and proliferating cell nuclear antigen staining as compared to unstimulated animals. In superovulated mice, an increase in the number of pro-inflammatory macrophages was detected in the oviduct. Ovulation also increased levels of phospho-γH2A.X in tubal epithelial cells, indicating that these cells were susceptible to double-strand DNA breakage following ovulation. To determine which components of ovulation contributed to DNA damage in the fallopian tube, an immortalized baboon tubal epithelial cell line and a three-dimensional organ culture system for mouse oviduct and baboon fallopian tubes were developed. Tubal epithelial cells did not proliferate or display increased DNA damage in response to the gonadotropins or estradiol alone in vitro. Oxidative stress generated by treatment with hydrogen peroxide or macrophage-conditioned medium increased DNA damage in tubal epithelial cells in culture. Ovulation may impact the fallopian tube epithelium by generating DNA damage and stimulating macrophage infiltration, but does not increase proliferation through gonadotropin signaling.
STAT3 offers an attractive target for cancer therapy but small molecule inhibitors with appealing pharmacologic properties have been elusive. Here we report hydroxamic acid-based and benzoic acid-based inhibitors (SH5-07 and SH4-54, respectively) with robust bioactivity. Both inhibitors blocked STAT3 DNA binding activity in vitro and in human glioma, breast, and prostate cancer cells and in v-Src-transformed murine fibroblasts. STAT3-dependent gene transcription was blocked along with Bcl-2, Bcl-xL, Mcl-1, Cyclin D1, c-Myc and Survivin expression. Nuclear magnetic resonance analysis of STAT3-inhibitor complexes defined interactions with the SH2 and DNA binding domains of STAT3. Ectopic expression of the SH2 domain in cells was sufficient to counter the STAT3 inhibitory effects of SH4-54. Neither compound appreciably affected STAT1 or STAT5 DNA binding activities, STAT3-independent gene transcription or activation of a panel of oncogenic kinases in malignant cells. Each compound decreased the proliferation and viability of glioma, breast and prostate cancer cells and v-Src-transformed murine fibroblasts harboring constitutively active STAT3. Further, in mouse xenograft models of glioma and breast cancer, administration of SH5-07 or SH4-54 effectively inhibited tumor growth. Our results offer preclinical proof of concept for SH5-07 and SH4-54 as candidates fof further development as cancer therapeutics.
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