Intra-tumoral heterogeneity has been shaping the field of precision medicine for cancer patients ever since its emergence. Prodrugs, which require activation by tumor associated enzymes (TAEs), are a rapidly emerging approach for targeted therapeutics. SULT1A1, a sulfotransferase enzyme and TAE, is over-expressed in about 5-15% of cancer patients including breast, prostate and renal cell carcinoma (RCC); however, it is either not expressed or expressed at low level in most normal tissue. Bioinformatic RNA analyses revealed that SULT1A1 over-expression in tumors is correlated with worse patient prognosis. We have identified a new compound, FIS103, which is a small molecule anti-cancer prodrug that is activated by SULT1A1 once internalized. This class of compounds, N-benzyl indole carbinols (N-BICs), cause rapid cell death by inducing widespread non-specific covalent alkylation of proteins in the cancer cell. We report that FIS103 displays potent antitumor activity in SULT1A1 over-expressing RCC cell lines (A498 and Caki-1). Contrarily, low SULT1A1 expressing RCC cells (786-O and ACHN) did not show any antitumor effects, which suggests low FIS103 toxicity in the absence of SULT1A1. In silico modeling validated the predicted SULT1A1-FIS103 interaction. Furthermore, FIS103 demonstrates potent SULT1A1-dependent antitumor activity in NU/J mouse xenografts injected with A498 cells. Remarkably, the flank tumors in mice regressed to non-measurable 14 days post-FIS103 treatment and did not regrow through the study conclusion. Additionally, SD rats treated with FIS103 once daily for 14 days demonstrated a promising liver toxicity profile with serum liver enzymes falling within the normal range and histopathology analysis indicated no difference between FIS103 or vehicle treated rats. We hereby demonstrate that FIS103 may have the potential to improve survival as well as quality of life of RCC patients and its application could be extended to other SULT1A1 expressing cancers.

The authors have declared no competing interest.

This study was funded by Fannin Partners, LLC.

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