Discovery of Deoxyadenosine Analogues as an Orally Bioavailable ADAR1 Modulator
Aihuan Wei, Wei Tang, Xiaoshuai Huang, Yuting Xu, Yihao Guo, Dongze Lin, Yanjie Ma, Congwei Chen, Jia Liu, Jian Ding, Yi Chen, Youhong HuAbstract
ADAR1 is an enzyme that catalyzes the conversion of adenosine to inosine, and its expression is dysregulated in various cancers. Based on the previously reported compound ZYS-1, we designed and synthesized a series of compounds to investigate structure–activity relationships (SAR) and identify novel adenosine analogues. Among these, compound H13 was found to exhibit potent antiproliferative activity against various cancer cell lines and selectively reduced ADAR1-mediated editing of APOBEC3D in a dose-dependent manner. Furthermore, compound H13 demonstrated favorable pharmacokinetic properties after oral administration (F = 31.97%) and significantly inhibited DU-145 and HUCCT1 tumor growth without apparent toxicities in vivo. These results support H13 as a promising lead compound for further development.