Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach
Muthuraj Prakash, Yukihiro Itoh, Yoshie Fujiwara, Yukari Takahashi, Yuri Takada, Paolo Mellini, Elghareeb E. Elboray, Mitsuhiro Terao, Yasunobu Yamashita, Chika Yamamoto, Takao Yamaguchi, Masayuki Kotoku, Yuki Kitao, Ritesh Singh, Rohini Roy, Satoshi Obika, Makoto Oba, Dan Ohtan Wang, Takayoshi Suzuki
Abstract
Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO-selective inhibitors.