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

Abstract

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.

• Authors: Yuki Hirose, Shinsuke Sato, Kaori Hashiya, Toshikazu Bando, Hiroshi Sugiyama
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 17 Pg. 12059-12068 (09 14 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 37606185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nylons
• Tumor Suppressor Protein p53
• Transcription Factors
• Imidazoles
• DNA
• Pyrroles

Topics

• Humans
• Animals
• Mice
• Nylons (pharmacology)
• Tumor Suppressor Protein p53 (genetics)
• Transcription Factors
• Pancreatic Neoplasms (drug therapy)
• Imidazoles
• DNA
• Pyrroles (pharmacology, therapeutic use)