Because of its key role in cancer development and progression, STAT3 has become an attractive target for developing new cancer therapeutics. While several STAT3 inhibitors have progressed to advanced stages of development, their underlying biology and mechanisms of action are often more complex than would be expected from specific binding to STAT3. Here, we have identified and optimized a series of compounds that block STAT3-dependent luciferase expression with nanomolar potency. Unexpectedly, our lead compounds did not bind to cellular STAT3 but to another prominent anticancer drug target, TrxR1. We further identified that TrxR1 inhibition induced Prx2 and STAT3 oxidation, which subsequently blocked STAT3-dependent transcription. Moreover, previously identified inhibitors of STAT3 were also found to inhibit TrxR1, and likewise, established TrxR1 inhibitors block STAT3-dependent transcriptional activity. These results provide new insights into the complexities of STAT3 redox regulation while highlighting a novel mechanism to block aberrant STAT3 signaling in cancer cells.

由于其在癌症发展和进程中的关键作用，STAT3已成为开发新的癌症疗法的有吸引力的靶标。尽管几种STAT3抑制剂已发展到晚期，但其潜在的生物学和作用机制通常比特异性结合STAT3所预期的更为复杂。在这里，我们已经确定并优化了一系列化合物，这些化合物可阻断STAT3依赖的萤光素酶表达，并具有纳摩尔浓度。出乎意料的是，我们的先导化合物并不结合细胞STAT3，而是结合到另一个重要的抗癌药物靶标TrxR1。我们进一步确定TrxR1抑制诱导Prx2和STAT3氧化，随后阻止了STAT3依赖性转录。此外，还发现先前确定的STAT3抑制剂可抑制TrxR1，同样，已建立的TrxR1抑制剂可阻断STAT3依赖性转录活性。这些结果为STAT3氧化还原调节的复杂性提供了新的见识，同时强调了阻断癌细胞中异常STAT3信号传导的新机制。