tasisulam (LY573636) / Eli Lilly - LARVOL DELTA

Targeting RBM39 with Tasisulam enhances TRAIL-induced apoptosis through DR5 upregulation and Bcl-2 downregulation in renal cell carcinoma. (PubMed, Biochem Pharmacol) - "These findings demonstrate that Tasisulam sensitizes RCC cells to TRAIL-induced apoptosis through RBM39-dependent DR5 upregulation and Bcl-2 downregulation. This combination strategy holds significant promise as a potential solution to overcoming TRAIL resistance and advancing more effective treatment outcomes for RCC."

Journal • B Cell Lymphoma • Genito-urinary Cancer • Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • RBM3 • RBM39 • TNFRSF10B

Recent advances in anticancer mechanisms of molecular glue degraders: focus on RBM39-dgrading synthetic sulfonamide such as indisulam, E7820, tasisulam, and chloroquinoxaline sulfonamide. (PubMed, Genes Genomics) - "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."

Journal • Review • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Hematological Malignancies • Metabolic Disorders • Neuroblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • RBM39

Multistep Continuous Flow Synthesis of Isolable NH2-Sulfinamidines via Nucleophilic Addition to Transient Sulfurdiimide. (PubMed, Chemistry) - "The transformation can additionally be realized under mild conditions, at room temperature, via a highly chemoselective halogen-lithium exchange of aryl bromides and iodides with n -butyllithium. Moreover, the synthetic potential of the methodology was assessed exploring further manipulations of the products and accessing novel S(IV) analogues of celecoxib, tasisulam, and relevant sulfinimidoylureas."

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A phase 2 study of tasisulam sodium (LY573636 sodium) as second-line treatment for patients with unresectable or metastatic melanoma (Cancer) -

P2, N=68; 8 pts showed partial response (PR) & 24 pts had stable disease (SD), ORR (CR + PR) was 11.8%, &  CRR (CR + PR + SD) was 47.1%; Median PFS 2.6 months & median OS 9.6 months; 20.6% pts showed grade 3/4 toxicity, thrombocytopenia

Melanoma

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. (PubMed, Nat Chem Biol) - "The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. We show that DCAF15 adopts a new fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrate how aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high-affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders."

Journal • Targeted Protein Degradation

Efficient synthesis of carbon-11 labelled acylsulfonamides using [C]CO carbonylation chemistry. (PubMed, Chem Commun (Camb)) - "Various model compounds as well as drug molecules LY573636 (tasisulam) and ABT-199 were obtained in excellent yields. This method provides a valuable and widely applicable contribution to the continuously expanding radiochemical toolbox for PET research."

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