Recent Advances of m6A Demethylases Inhibitors and Their Biological Functions in Human Diseases

Abstract

N6-methyladenosine (m6A) is a post-transcriptional RNA modification and one of the most abundant types of RNA chemical modifications. m6A functions as a molecular switch and is involved in a range of biomedical aspects, including cardiovascular diseases, the central nervous system, and cancers. Conceptually, m6A methylation can be dynamically and reversibly modulated by RNA methylation regulatory proteins, resulting in diverse fates of mRNAs. This review focuses on m6A demethylases fat-mass- and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), which especially erase m6A modification from target mRNAs. Recent advances have highlighted that FTO and ALKBH5 play an oncogenic role in various cancers, such as acute myeloid leukemias (AML), glioblastoma, and breast cancer. Moreover, studies in vitro and in mouse models confirmed that FTO-specific inhibitors exhibited anti-tumor effects in several cancers. Accumulating evidence has suggested the possibility of FTO and ALKBH5 as therapeutic targets for specific diseases. In this review, we aim to illustrate the structural properties of these two m6A demethylases and the development of their specific inhibitors. Additionally, this review will summarize the biological functions of these two m6A demethylases in various types of cancers and other human diseases.

The emerging roles and mechanism of m6a in breast cancer progression

“…Secondly, the primary prerequisite for targeting m6A-modified enzymes is the resolution of the protein crystal complexes of these enzymes in order to mine and design docked high-affinity small molecules and antibodies by conformational relationships ( Oerum et al, 2021 ). These inhibitors and antibodies, in turn, will be considered to provide a good pre-requisite for clinical targeting only after effective validation in cellular and animal experiments ( You et al, 2022 ). Finally, numerous studies have explained the critical role of m6A recognition proteins in BC, but a considerable number of m6A regulators have not been fully validated, including RBM15/RBM15B, HAKAI, ZC3H13, ALKBH3, eIF3, hnRNPC, and hnRNPA2B1.…”

Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases

“…A number of compounds targeting m 6 A writers 345 , 393 and erasers 394 , 395 , 396 have been identified. A summary of these small molecules is provided in Table S5 .…”

“…Drugging the m 6 A-and A-to-I-related pathways in cardiovascular diseases A number of compounds targeting m 6 A writers 345,393 and erasers [394][395][396] have been identified. A summary of these small molecules is provided in Table S5.…”

Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia

“…Collectively, with a minor influence on normal hematopoiesis, ALKBH5 is considered as a crucial therapeutic target for leukemia. The crystallographic and biochemical studies indicated that the ALKBH5 inhibitors may be smaller in size than those for FTO, due to its smaller active cavity [142]. Selberg et al assessed the antiproliferative effects of ALKBH5 inhibitors and discovered two compounds with potent inhibition against the proliferation of three leukemia cell lines, demonstrating the value of ALKBH5 inhibitor as an anti-leukemia strategy [143].…”