Anticancer Activities of DNA-Alkylating Pyrrole–Imidazole Polyamide Analogs Targeting RUNX Transcription Factors against p53-Mutated Pancreatic Cancer PANC‑1 Cells

The runt-related transcription factor (RUNX) family is known to play important roles in the progression of cancer. Conjugate 1, which covalently binds to the RUNX-binding sequences, was reported to inhibit the binding of RUNX proteins to their target sites and suppress cancer growth. Here, we evaluated the anticancer effects of 1 and its analogs 2–4 against p53-mutated PANC-1 pancreatic cancer cells. We found that they possessed different DNA-alkylating properties in vitro. And conjugates 1–3 were shown to have anticancer effects by inducing apoptosis in PANC-1 cells. Furthermore, conjugates 2 and 3 suppressed cancer growth in PANC-1 xenograft mice, with activity equivalent to a 50-fold dose of gemcitabine. Especially, 3 showed the highest alkylation efficiency, specificity, and better anticancer effects against pancreatic cancer than 1 in vivo without significant body weight loss. Our results revealed the potential of our compounds as new candidates for cancer therapy.

runt相关转录因子（runt-related transcription factor, RUNX）家族已知在癌症进展中发挥关键作用。可与RUNX结合序列共价结合的缀合物1，已有研究表明可抑制RUNX蛋白与其靶位点的结合并阻断癌症生长。本研究针对p53突变型PANC-1胰腺癌细胞，评估了缀合物1及其类似物2~4的抗癌活性。实验发现，这些化合物在体外展现出各不相同的DNA烷基化特性。研究证实，缀合物1~3可通过诱导PANC-1细胞凋亡发挥抗癌作用。此外，缀合物2和3可在PANC-1细胞异种移植瘤小鼠模型中抑制癌症生长，其活性相当于50倍剂量的吉西他滨（gemcitabine）。尤为值得注意的是，缀合物3的烷基化效率与特异性均为最高，且在体内抗胰腺癌活性优于缀合物1，同时未引发显著的体重下降。本研究结果证实，这类化合物有望成为癌症治疗的新型候选药物。