Targeting SETD2 in Cancer therapy: Structure, biological functions, and inhibitor development.

SET domain-containing protein 2 (SETD2) is the only methyltransferase that catalyzes the trimethylation of lysine at position 36 of histone H3 (H3K36me3), playing a vital role in correcting base mismatches and repairing DNA damage during gene replication and transcription. Therefore, it ensures the stability of the genome. The AWS-SET-PostSET domains within SETD2 play a pivotal role in gene mismatch repair, regulating cellular differentiation and apoptosis. However, mutations frequently occur in the AWS-SET-PostSET domains, leading to abnormal expression of H3K36me3 and promoting tumorigenesis and disease progression. Therefore, SETD2 has emerged as a significant target for clinical diagnosis and cancer therapy. This article introduces the domains and functions of the SETD2 protein, further elucidating its role in the initiation and development of cancer. It explores the roles and differences of SETD2 and its family proteins in cancer. Additionally, the article elucidates existing SETD2 inhibitors, introduces two important inhibitor core structures (methylindole scaffold and sinefungin analogs), and summarizes their structure-activity relationships (SARs). This review outlines the structural mechanisms by which inhibitors target SETD2, highlighting interactions with specific amino acids. By analyzing the SARs of inhibitors, we provide recommendations for drug design targeting SETD2 inhibitors, emphasizing the importance of the rigid chair conformation of the cyclohexyl structure to binding. This review aims to serve as a reference for the development of novel SETD2 inhibitors.