2. Academic Validation
  3. Rational Design and Optimization of m6A-RNA Demethylase FTO Inhibitors as Anticancer Agents

Rational Design and Optimization of m6A-RNA Demethylase FTO Inhibitors as Anticancer Agents

  • J Med Chem. 2022 Aug 25;65(16):10920-10937. doi: 10.1021/acs.jmedchem.1c02075.
Sarah Huff 1,  Indrasena Reddy Kummetha 1,  Lingzhi Zhang 1,  Lingling Wang 1,  William Bray 1,  Jiekai Yin 2,  Vanessa Kelley 1,  Yinsheng Wang 2,  Tariq M Rana 1 3
Affiliations

Affiliations

  • 1 Division of Genetics, Department of Pediatrics, Center for Drug Discovery Innovation, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive MC 0762, La Jolla, California 92093, United States.
  • 2 Environmental Toxicology Graduate Program and Department of Chemistry, University of California, Riverside, California 92521, United States.
  • 3 San Diego Center for Precision Immunotherapy, Moores Cancer Center 3855 Health Sciences Drive, University of California San Diego, La Jolla, California 92093, United States.
PMID: 35939803 DOI: 10.1021/acs.jmedchem.1c02075
Abstract

Aberrant regulation of N6-methyladenosine (m6A) RNA modification has been implicated in the progression of multiple diseases, including Cancer. Previously, we identified a small molecule inhibitor of the m6A demethylase fat mass- and obesity-associated protein (FTO), which removes both m6A and N6,2'-O-dimethyladenosine (m6Am) RNA modifications. In this work, we describe the rational design and optimization of a new class of FTO inhibitors derived from our previous lead FTO-04 with nanomolar potency and high selectivity against the homologous m6A RNA demethylase ALKBH5. The oxetanyl class of compounds comprise competitive inhibitors of FTO with potent antiproliferative effects in glioblastoma, acute myeloid leukemia, and Gastric Cancer Models where lead FTO-43 demonstrated potency comparable to clinical chemotherapeutic 5-fluorouracil. Furthermore, FTO-43 increased m6A and m6Am levels in a manner comparable to FTO knockdown in gastric Cancer cells and regulated Wnt/PI3K-Akt signaling pathways. The oxetanyl class contains significantly improved Anticancer agents with a variety of applications beyond glioblastoma.

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