Research Progress on Splicing‑Factor‑Targeted Inhibitors in Hematologic Malignancies

Abstract

Pre‑mRNA splicing is a central regulatory step in eukaryotic gene expression. Splicing factor genes (such as splicing factor 3B subunit 1 [SF3B1], U2 small nuclear RNA auxiliary factor 1 [U2AF1], and serine/arginine-rich splicing factor 2 [SRSF2]) are frequently mutated in hematologic malignancies and have emerged as key oncogenic drivers and highly promising therapeutic targets [1][2]. In recent years, breakthroughs in cryo‑electron microscopy have enabled near‑atomic‑resolution structural determination of the spliceosome in various functional states [3][4], providing precise molecular blueprints for structure‑based drug design and fundamentally overturning the long‑held view of the spliceosome as an “undruggable” target. This article systematically reviews the structural features, hotspot mutations, and oncogenic mechanisms of the three major splicing factors SF3B1, U2AF1, and SRSF2. It focuses on the development of spliceosome‑targeted inhibitors driven by structural biology, including SF3B1‑targeting agents (Pladienolide B, E7107, H3B‑8800), U2AF1‑targeting agents (SF1‑8/AP232), SRSF2‑targeting strategies (ROCK inhibitors, PRMT5 inhibitors, PARP inhibitors), and inhibitors of the common downstream pathway (IRAK4 inhibitors Emavusertib and R289). The article further analyzes the clinical trial status, core challenges, and future directions for each inhibitor class, aiming to provide a reference for research and clinical practice in this field.