m6A modification: recent advances, anticancer targeted drug discovery and beyond

Abstract

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Keywords: Cancer; Chemosynthesis; Drug discovery; Modulators; Natural product; m6A.

Fig. 1

The underlying mechanisms of m6A modification. The m6A modification of mRNA is mainly catalyzed by the core methylase complex METTL3-WTAP-METTL14. RBM15/15B, VIRMA/KIAA1429, and ZC3H13 are newly identified mRNA m6A writers; METTL4, and METTL16 are snRNA m6A writhers; and METTL5 and ZCCHC4 are rRNA m6A writers. The m6A modification is removed by FTO, ALKBH5, and ALKBH3. Readers recognize m6A and affect various functions of RNAs, and they mainly include members of the YTH domain-containing family, the IGF2BP family, the HNRNP family, eIF3, PRRC2A, and FMRP

Fig. 2

The role of m6A in human cancers. m6A modification regulators affect the progression of different types of human cancers by functioning as either tumor promoters or tumor suppressors. Abbreviations: AML, Acute myeloid leukemia; BLC, Bladder cancer; BC, Breast cancer; CRC, Colorectal cancer; GC, Gastric cancer; GBM, Glioblastoma; HCC, Hepatocellular carcinoma; HNSCC, Head and neck squamous cell carcinoma; MM, Multiple myeloma; LC, Lung carcinoma; OS, Osteosarcoma; OC, Ovarian cancer; PAAD, Pancreatic adenocarcinoma; PRAD, Prostate adenocarcinoma; RB, Retinoblastoma; RCC, Renal cell carcinoma

Fig. 3

The chemical structures of natural products regulating m6A modification. A Phenols, B flavonoids, C alkaloids, D anthraquinone, E terpenoids, and F other natural products

Fig. 4

The chemical structures of lead compounds targeting m6A regulators from AI-based approaches. A Compounds targeting FTO derived from MA. B Compounds targeting FTO derived from the structure-based strategy. C Compounds targeting ALKBH5. D Compounds targeting METTL3

Fig. 5

A framework for the m6A-targeting drug discovery through integration of AI and traditional medicines and natural products. The data collected and organized from protein databases and compound libraries were performed with high-throughput virtual screening, followed by screening and predication, modification and optimization of chemical structures, and assessment of druggability of lead compounds that target m6A modification