Abstract 1651: Discovery of oridonin-based proteolysis targeting chimera (PROTAC) compounds as putative protein degraders and potent anticancer agents for triple-negative breast cancer

Abstract

Abstract Natural products provide a molecular starting point for the development of novel therapeutic agents including a plethora of anti-cancer drugs currently in use. Oridonin is a natural diterpene compound enriched in medicinal herb Rabdosia rubescens, and its unique anti-cancer properties have been extensively studied. However, clinical applications of oridonin are limited due to its relatively low potency. Previously, we developed a class of druglike nitrogen-enriched oridonin derivatives, including CYD0618 and others, with thiazole modifications as effective anticancer agents to inhibit breast cancer growth in vitro and in vivo. Although breast cancer screening and treatments have improved over the last half-century, aggressive subtypes like triple-negative breast cancer (TNBC) are refractory to frontline therapies, in which the STAT3 transcription factor plays a key role in developing therapeutic resistance and recurrence. Currently, there are no FDA-approved direct STAT3 inhibitors in clinical use. We reported that CYD0618 inhibits STAT3 signaling, likely through a direct interaction with STAT3. With proteolysis targeting chimera (PROTAC) technology, our team designed novel oridonin- and CYD0618-based PROTAC compounds including PW0965 and PW1087 in an attempt to achieve STAT3 binding and degradation. We determined anticancer effects of PW0965 and PW1087 on proliferation, colony formation, apoptosis and cell motility of triple-negative breast cancer (TNBC) cells MDA-MB-231 and BT549. We found that both compounds significantly inhibited the proliferation of TNBC cells. Compared with oridonin, both compounds more effectively induced apoptosis of TNBC cells. Additionally, MDA-MB-231 and BT549 cells treated with these PROTACs showed significantly reduced migration and invasion compared to control cells. PW0965 and PW1087 treatment reduced protein levels of STAT3 and its activation at Y705 residue in TNBC cells as early as 4 hours of treatment. This observed reduction in STAT3 protein on Western blot exhibited dose and time dependence. Collectively, our results demonstrate that oridonin and its analog-based PROTACs exhibit excellent potency against TNBC cells, likely through protein degradation of STAT3. The potency of PW0965 and PW1087 warrants further in vitro and in vivo investigation in cancer cells and tumor xenograft models. The molecular profiles of these PROTACs, including their interactions with STAT proteins and protein degradation, are currently under investigation. Citation Format: Ruixia Ma, Jun Li, Gabrielle R. Vontz, Pingyuan Wang, Haiying Chen, Jia Zhou, Qiang Shen. Discovery of oridonin-based proteolysis targeting chimera (PROTAC) compounds as putative protein degraders and potent anticancer agents for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1651.