Aberrant regulation of <i>N</i><sup>6</sup>-methyladenosine (m<sup>6</sup>A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m<sup>6</sup>A demethylase fat mass- and obesity-associated protein (FTO), which removes both m<sup>6</sup>A and <i>N</i><sup>6</sup>,2'-<i>O</i>-dimethyladenosine (m<sup>6</sup>A<sub>m</sub>) 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 m<sup>6</sup>A 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 m<sup>6</sup>A and m<sup>6</sup>A<sub>m</sub> 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.