Tasisulam Sodium

Synthetic sulfonamide anticancer drugs, including E7820, indisulam, tasisulam, and chloroquinoxaline sulfonamide, exhibit diverse mechanisms of action and therapeutic potential, functioning as molecular glue degraders. E7820 targets RBM39, affecting RNA splicing and angiogenesis by suppressing integrin α2. Phase I studies have demonstrated some stability in advanced solid malignancies; however, further efficacy studies are required. Indisulam causes G1 cell cycle arrest and delays the G1/S transition by modulating splicing through RBM39 degradation via DCAF15. Despite its limited initial efficacy, it shows promise in combination therapies, particularly for hematopoietic malignancies and gliomas. Tasisulam inhibits VEGF signaling, suppresses angiogenesis, and induces apoptosis. Although early trials indicated broad activity, safety concerns have halted its development. Chloroquinoxaline sulfonamide, initially investigated for cell cycle arrest and topoisomerase II inhibition, was discontinued owing to its limited efficacy and toxicity, despite promising initial results. Recent studies revealed the structural interaction of E7820 with DCAF15 and RBM39, although phase II trials on myeloid malignancies have shown limited efficacy. Indisulam is effective against glioblastoma and neuroblastoma, with potential synergy in combination therapies and metabolic disruption. Recent research on tasisulam reveals its potential in cancer therapy by targeting RBM39 degradation through DCAF15-mediated pathways. Understanding these mechanisms could lead to new treatments that affect alternative splicing and improve cancer therapies Overall, although these drugs exhibit promising mechanisms of action, further research is required to optimize their clinical efficacy and safety.

It has been revealed recently that the RNA-binding motif protein RBM39 is highly expressed in several cancers, which results in poor patient survival. However, how RBM39 is regulated in gastric cancer cells is unknown. Here, affinity purification-mass spectrometry and a biochemical screening are employed to identify the RBM39-interacting proteins and the deubiquitinating enzymes that regulate the RBM39 protein level. Integration of the data obtained from these two approaches uncovers USP39 as the potential deubiquitinating enzyme that regulates RBM39 stability. Bioinformatic analysis discloses that USP39 is increased in gastric cancer tissues and its elevation shortens the duration of overall survival for gastric cancer patients. Biochemical experiments verify that USP39 and RBM39 interact with each other and highly colocalize in the nucleus. Expression of USP39 elevates while USP39 knockdown attenuates the RBM39 protein level and their interaction regulates this modulation and their colocalization. Mechanistic studies reveal that USP39 reduces the K48-linked polyubiquitin chains on RBM39, thus enhancing its stability and increasing the protein level by preventing its proteasomal degradation. USP39 overexpression promotes while its knockdown attenuates the growth, colony formation, migration, and invasion of gastric cancer cells. Interestingly, overexpression of RBM39 partially restores the impact of USP39 depletion, while RBM39 knockdown partially abolishes the effect of USP39 overexpression on the growth, colony formation, migration, and invasion of gastric cancer cells. Collectively, this work identifies the first DUB for RBM39 and elucidates the regulatory functions and the underlying mechanism, providing a possible alternative approach to suppressing RBM39 by inhibiting USP39 in cancer therapy.