herboxidiene

Herboxidiene (GEX1A) is a natural polyketide isolated from *Streptomyces chromofuscus* that acts as a potent small molecule spliceosome modulator. It exerts its biological activity by specifically binding to the SAP155 subunit of the Splicing Factor 3B subunit 1 (SF3B1), a component of the U2 small nuclear ribonucleoprotein (snRNP) complex. This binding interferes with the recognition of the branch point adenosine during pre-mRNA splicing. In the context of oncology, particularly hematologic malignancies like acute myeloid leukemia (AML), herboxidiene induces a splice isoform shift of the anti-apoptotic protein MCL-1 to its pro-apoptotic variant, MCL-1S. It also facilitates the conversion of pro-survival BCL-2 into a pro-apoptotic mediator through interactions with the orphan nuclear receptor Nur77 (NR4A1) and represses the expression of oncogenic drivers such as FLT3-ITD. Additionally, it has been shown to target leukemia stem cells by inhibiting the mitochondrial isoform of FASTK. Beyond oncology, research suggests herboxidiene may have utility in treating Niemann-Pick type C1 by correcting associated cellular defects.

Other names

GEX1AGEX-1AGEX 1A