2. Academic Validation
  3. Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach

Identification of Potent and Selective Inhibitors of Fat Mass Obesity-Associated Protein Using a Fragment-Merging Approach

  • J Med Chem. 2021 Nov 11;64(21):15810-15824. doi: 10.1021/acs.jmedchem.1c01107.
Muthuraj Prakash 1,  Yukihiro Itoh 1 2,  Yoshie Fujiwara 3,  Yukari Takahashi 1,  Yuri Takada 2,  Paolo Mellini 1,  Elghareeb E Elboray 1 4,  Mitsuhiro Terao 2,  Yasunobu Yamashita 2,  Chika Yamamoto 5,  Takao Yamaguchi 5,  Masayuki Kotoku 1,  Yuki Kitao 1,  Ritesh Singh 1 6,  Rohini Roy 3 7,  Satoshi Obika 5,  Makoto Oba 1,  Dan Ohtan Wang 3 8 9,  Takayoshi Suzuki 1 2 10
Affiliations

Affiliations

  • 1 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan.
  • 2 SANKEN, Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
  • 3 Institute for Integrated Cell-Material Sciences (iCeMS), Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto 606-8501, Japan.
  • 4 Chemistry Department, Faculty of Science, South Valley University, Qena 83523, Egypt.
  • 5 Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 6 Department of Chemistry, Central University of Rajasthan, NH-8, Bandar Sindri, Ajmer 305817, Rajasthan, India.
  • 7 Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
  • 8 Center for Biosystems Dynamics Research, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
  • 9 Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 10 CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
PMID: 34727689 DOI: 10.1021/acs.jmedchem.1c01107
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.

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