Triple-negative breast cancer (TNBC) is an aggressive malignancy with poor clinical outcomes. YD277 is a novel small molecule derived from ML264, a KLF5 inhibitor that elicits cytotoxic effects in colon cancer cell lines. Our previous studies suggest that Krüpple-like factor 5 (KLF5) is a promising therapeutic target for TNBC. In this study, we demonstrated that YD277 significantly induced G1 cell cycle arrest and apoptosis in MDA-MB-231 and MDA-MB-468 TNBC cells, independent of KLF5 inhibition. YD277 also reduced the protein expression levels of Cyclin D1, Bcl2 and Bclxl and promoted the expression of p21 and p27. Moreover, the pro-apoptotic activity of YD277 in TNBC was mediated by the transcription of IRE1α, a key molecule in the endoplasmic reticulum (ER) stress pathway. Finally, YD277 (15 mg/kg) significantly suppressed the growth of MDA-MB-231 tumor xenografts in nude mice. These findings indicate that YD277 is a promising chemotherapeutic candidate for TNBC.

中文翻译：

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YD277 部分通过激活内质网应激途径抑制三阴性乳腺癌

三阴性乳腺癌（TNBC）是一种侵袭性恶性肿瘤，临床结果不佳。YD277 是一种源自 ML264 的新型小分子，ML264 是一种 KLF5 抑制剂，可在结肠癌细胞系中引发细胞毒性作用。我们之前的研究表明 Krüpple 样因子 5 (KLF5) 是 TNBC 的一个有前途的治疗靶点。在这项研究中，我们证明 YD277 显着诱导 MDA-MB-231 和 MDA-MB-468 TNBC 细胞的 G1 细胞周期停滞和凋亡，与 KLF5 抑制无关。YD277还降低Cyclin D1、Bcl2和Bclxl的蛋白表达水平，并促进p21和p27的表达。此外，YD277 在 TNBC 中的促凋亡活性是由 IRE1α 的转录介导的，IRE1α 是内质网 (ER) 应激途径中的关键分子。最后，YD277（15 mg/kg）显着抑制裸鼠中MDA-MB-231肿瘤异种移植物的生长。这些发现表明，YD277 是一种有前途的 TNBC 化疗候选药物。