用于治疗MYC驱动型癌症的首创YTHDC1小分子抑制剂的发现

The m6A reader protein YTHDC1 is essential for cancer cell survival, through its ability to form nuclear biomolecular condensates that stabilize oncogenic transcripts such as MYC . Here, we report a new class of potent, selective, orally bioavailable small-molecule inhibitors of YTHDC1. These compounds occupy the RNA binding pocket of YTHDC1 and disrupt its interaction with m 6 A-modified RNA at nanomolar potency in both biochemical and cellular assays. They display high selectivity for YTHDC1 over other YTH family members, selectively dissolve m6A-dependent YTHDC1 condensates without affecting unrelated condensate systems, and exhibit clean profiles across broad kinase and safety panels. The optimized leads are drug-like, orally bioavailable and possess favorable ADME and in vivo properties. Pharmacological inhibition of YTHDC1 disrupts oncogenic YTHDC1 condensates and robustly suppresses MYC signaling resulting in growth arrest, differentiation, and apoptosis of acute myeloid leukemia (AML) and additional cancer cell types, while sparing normal hematopoietic cells. These optimized inhibitors display strong single-agent anti-tumor activity across heme and solid tumor models including AML, small cell lung cancer and neuroendocrine prostate cancer. Moreover, YTHDC1 inhibition shows pronounced synergy with standard of care agents such as venetoclax in AML. Collectively, these findings establish YTHDC1 as a tractable therapeutic target for MYC-driven malignancies.