Indisulam
RBM39 Molecular glue / Indisulam was originally described as a potent antitumor agent that targeted the G1 phase of cell cycle via suppression of activation of CDK2 and cyclin E expression.1 More recently it has been found to act as a molecular glue promoting the recruitment of RNA binding motif protein 39 (RBM39) to the CUL4-DCAF15 E3 ubiquitin ligase leading to proteasomal degradation.2 Removal of splicing factor RBM39 leads to altered RNA splicing and death in multiple cancer cell lines – Indisulam alters the expression of more than 3000 genes and causes widespread intron retention and exon skipping.3 It induced metabolome perturbations and mitochondrial dysfunction in neuroblastoma models leading to complete tumor regression without relapse.4 Arginine has been found to bind to RBM39 causing reprogramming of metabolic genes to promote tumor growth – indisulam treatment leading to RBM39 degradation mimics arginine depletion resulting in reduced growth in patient-derived hepatocellular carcinoma organoids.5
Biochemicals & reagents
165668-41-7
E7070
1) Owa et al. (1999), Discovery of Novel Antitumor Sulfonamides Targeting G1 Phase of the Cell Cycle; J. Med. Chem. 42 3789 2) Ting et al. (2017); Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15, Science, 356 eaal3755 3) Ting et al. (2019); Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15, Cell Rep., 29 1499 4) Nijhuis et al. (2022); Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma, Nat. Commun., 13 1380 5) Mossmann et al. (2023), Arginine reprograms metabolism in liver cancer via RBM39; Cell 186 P5068
-20°C
TARGET: Molecular glue; Ubiquitin ligase; RNA -- PATHWAY: Mitochondrial function; Cell cycle; Degradation -- DISEASE AREA: Cancer