Abstract 814: A novel small molecule prodrug activated inside cancer cells by a tumor associated enzyme for targeted chemotherapeutics in kidney cancer
Authors: Ross A. Hamilton, Leniher C. Chibas, Uksha Saini, Stephanie Vega, Dev Chatterjee, Atul Varadhachary
Journal: Cancer Research (2025)

Abstract Significance: Brimstalt Therapeutics is developing a small molecule drug for treatment of cancer patients with tumors that express the tumor associated enzyme (TAE), SULT1A1. The lead compound, BST-12, is a prodrug that is activated by SULT1A1, converting it into a potent non-specific alkylating agent resulting in targeted cancer cell death while leaving normal tissue unaffected. BST-12 belongs to a class of compounds called N-Benzyl Indole Carbinols (N-BICs). N-BICs have been previously identified as compounds that demonstrate potent antitumor effects once activated by SULT1A1, whose expression is both necessary and sufficient for activation. Kidney and renal pelvis cancer is the seventh most common cancer in the US, with an estimated 82, 610 new cases and 14, 390 deaths in 2024. Renal cell carcinoma (RCC) is the most frequent type of renal cancer; unfortunately, 33% of patients will experience relapse at metastatic sites and, consequently, have significantly poorer outcomes, highlighting the urgent need for novel therapeutic strategies. SULT1A1 is a metabolic sulfotransferase that is normally expressed in the liver, kidney, and GI tract, and either not expressed or expressed at low levels in other tissue types. However, SULT1A1 is a known inducer of carcinogenesis, considered a TAE that is over-expressed in about 8-15% of major cancers, including RCC, breast, and prostate, and its expression correlates with poorer patient prognosis. An IHC study on 233 tumors from 48 tissue types showed that in RCC, SULT1A1 levels were elevated and homogenously expressed; thus, RCC was selected for the initial indication for BST-12 testing. Results: In preclinical studies, BST-12 demonstrates potent anticancer activity in SULT1A1+ RCC cells (A498 and Caki-1), with IC50s under 250 pM, but has no effect on SULT1A1- cells (ACHN and 786-0). Direct sulfonation assays using recombinant SULT1A1 protein supports the mechanism of action reported with N-BICs. Furthermore, BST-12 treated A498 and Caki-1 cells had increased phospho-H2A.X levels, a DNA-damage marker associated with non-specific alkylation, topoisomerase inhibitors, and ROS inducing agents. In vivo, BST-12 treatment in A498 CDX models rapidly eliminated established tumors. To assess toxicity, the organs (liver, kidney, GI tract), serum liver enzyme levels (AST, ALT), and body weights of male/female rats treated with BST-12 were evaluated and indicated BST-12 has a good tolerability profile. Conclusions: The development of BST-12 has significant potential to improve survival / quality of life of SULT1A1+ RCC cancer patients. Although RCC is our primary target indication, the initial BST-12 proof-of-concept will support label expansion opportunities in other SULT1A1+ cancer types. Lastly, BST-12 has intriguing promise for bypassing any acquired resistance pathways associated with current standards of care. Citation Format: Ross A. Hamilton, Leniher C. Chibas, Uksha Saini, Stephanie Vega, Dev Chatterjee, Atul Varadhachary. A novel small molecule prodrug activated inside cancer cells by a tumor associated enzyme for targeted chemotherapeutics in kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 814.