Chb-M', an Inhibitor of the RUNX Family Binding to DNA, Induces Apoptosis in p53-Mutated Non-Small Cell Lung Cancer and Inhibits Tumor Growth and Repopulation In Vivo.

Runt-related transcription factor (RUNX) proteins are considered to play various roles in cancer. Here, we evaluated the anticancer activity of Chb-M', a compound that specifically and covalently binds to the consensus sequence for RUNX family proteins, in p53-mutated non-small cell lung cancer cells. Chb-M' killed the cancer cells by inducing apoptosis. The compound showed an anticancer effect comparable to that of the clinically used drugs alectinib and ceritinib in vivo. Notably, Chb-M' extended the cancer-free survival of mice after ending treatment more effectively than did the other two drugs. The results presented here suggest that Chb-M' is an attractive candidate as an anticancer drug applicable to the treatment of non-small cell lung cancer and various other types of cancers.

A dual DNA-binding conjugate that selectively recognizes G-quadruplex structures.

G-quadruplex (G4) structures play roles in various biological processes, but the challenge lies in specific targeting. To address this, we synthesized a conjugate capable of recognizing the G4 structure and its proximal duplex. Our conjugate can enable recognition of specific G4s in the human genome to understand and target those structures.

Structural Studies of a Complex of a CAG/CTG Repeat Sequence-Specific Binding Molecule and A-A-Mismatch-Containing DNA.

Triplet repeat diseases are caused by the abnormal elongation of repeated sequences comprising three bases. In particular, the elongation of CAG/CTG repeat sequences is thought to result in conditions such as Huntington's disease and myotonic dystrophy type 1. Although the causes of these diseases are known, fundamental treatments have not been established, and specific drugs are expected to be developed. Pyrrole imidazole polyamide (PIP) is a class of molecules that binds to the minor groove of the DNA duplex in a sequence-specific manner; because of this property, it shows promise in drug discovery applications. Earlier, it was reported that PIP designed to bind CAG/CTG repeat sequences suppresses the genes that cause triplet repeat diseases. In this study, we performed an X-ray crystal structure analysis of a complex of double-stranded DNA containing A-A mismatched base pairs and a cyclic-PIP that binds specifically to CAG/CTG sequences. Furthermore, the validity and characteristics of this structure were analyzed using in silico molecular modeling, ab initio energy calculations, gel electrophoresis, and surface plasmon resonance. With our direct observation using atomic force microscopy and DNA origami, we revealed that the PIP caused structural changes in the DNA strands carrying the expanded CAG/CTG repeat. Overall, our study provides new insight into PIP from a structural perspective.