The runt-related transcription factor (RUNX) family members regulate the expression of downstream genes by binding to their consensus binding sequences and have been reported to play important roles in various types of cancer. Based on the function of the RUNX family in cancer proliferation, we previously designed conjugate 1 (Figure)¹. Conjugate 1 recognizes the RUNX-binding site through its DNA-binding pyrrole−imidazole polyamide (PIP) moiety following a unique recognition rule: an antiparallel pair of N-methylpyrrole (Py)/N-methylimidazole (Im) is specific for a C/G base pair, whereas a Py/Py pair is specific for an A/T or T/A base pair. And 1 has a DNA alkylating chlorambucil moiety on its N-terminus, which forms a covalent bond with an A or G base of DNA and makes 1's binding irreversible. As a result, conjugate 1 has been reported to specifically bind to the RUNX-target sequence, inhibit the expression of RUNX family-dependent genes, and suppress cancer growth in various cancer models.
In this study, we prepared conjugate 1 and its analogs, which recognize the same sequence in different binding modes. We evaluated their sequence specificities and anti-cancer effects against pancreatic cancer, one of the highly lethal types of cancer. We found that two analogs possessed improved alkylation specificity compared to conjugate 1. Remarkably, one of them showed better anti-cancer effects in vivo than conjugate 1 and gemcitabine, a clinically used drug, without significant body weight loss. Our results suggest the potential of the compound as a new candidate for cancer therapy. Details of our research will be presented here.