DIQ01 is a specific small-molecule inhibitor of KH-type splicing regulatory protein (KHSRP), targets KH3 domain of KHSRP (MST Kd=387.4 nM) and disrupts RNA binding, exhibits potent antitumor efficacy.
DIQ01 exhibits superior activity against three distinct cancer cell lines, with IC50 of 64.7 nM for HCT116 colorectal cancer model.
DIQ01 functionally inactivates KHSRP, triggering destabilization and downregulation of its target PLK1 mRNA.
DIQ01 induces irreparable DNA damage in cancer cells, induces S-phase arrest in HCT116 colorectal cancer cells, significantly decreases the expression levels of key cell cycle and proliferation-regulatory proteins, such as CDK2, CDK4, and c-Myc, while upregulating p53 in a dose-dependent manner.
DIQ01 targets the KH3 domain of KHSRP and disrupts RNA binding, disrupts KHSRP-RNA binding in a concentration-dependent manner with IC50 values of 2.82 uM for full-length KHSRP.
DIQ01 inhibits PRMT5-mediated methylation of KHSRP.
DIQ01 (3-6 mg/kg, i.v.) suppresses KHSRP-dependent colorectal cancer growth in vivo, exhibits robust antiproliferative activity with IC50 of 0.85 uM for patient-derived colorectal cancer organoid models.
KHSRP is a multifunctional RNA-binding protein that promotes the decay of AU-rich element (ARE)-containing mRNAs and regulates microRNA biogenesis.