Indisulam | RBM39 Molecular glue

Indisulam (165668-41-7) 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

References/Citations:

1. Owa et al. (1999), Discovery of Novel Antitumor Sulfonamides Targeting G1 Phase of the Cell Cycle; J. Med. Chem. 42 3789
2. Han 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 targtets 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