Abstract Natural products provide a wealth of resources as the molecular starting point for the development of therapeutic agents, including a plethora of anticancer drugs currently in clinical use. Oridonin is a natural diterpene compound enriched in the medicinal herb Rabdosia rubescens, and its anticancer property has been extensively studied. However, the potency of oridonin against triple-negative breast cancer (TNBC) limits its potential clinical translation. Previously, we developed a class of oridonin analogues including CYD0618 and others as effective anticancer agents to inhibit tumor growth of TNBC in vitro and in vivo. Intriguingly, CYD0618 has been shown to directly bind to and inhibit STAT3 transcription factor, which is constitutively activated in the majority of human cancers. Currently there are no FDA-approved direct STAT3 inhibitors in clinical use. Based on the proteolysis-targeting chimera (PROTAC) technology, our team designed novel oridonin- and CYD0618-based PROTACs in an attempt to achieve specific STAT3 binding and protein degradation. We determined anticancer effects of oridonin- and CYD0618-PROTACs on proliferation, colony formation, and apoptosis of the TNBC cell line MDA-MB-231. We found that oridonin- and CYD0618-based PROTACs inhibited the proliferation of MDA-MB-231 cells significantly, similarly effective as the lead compound CYD0618 and much more potent than oridonin. We then examined the expression of STAT3, pSTAT3 and protein biomarkers for tumor metastasis using Western blot. STAT3 and pSTAT3 protein levels were downregulated dose- and time-dependently in MDA-MB-231 cells treated with CYD0618 and CYD0618-PROTACs, respectively. Our results demonstrate impressive effects of CYD0618-based PROTACs against TNBC cells, primarily through direct targeting of STAT3. We are in the process of further characterizing the molecular profile of CYD0618-based PROTACs by studying its interaction with STAT3 and protein degradation as well as their efficacy against TNBC tumor xenografts in vivo. Citation Format: Ruixia Ma, Pingyuan Wang, Junhai Xu, Jimin Xu, Doerte R. Fricke, Yu Xue, Hyejin Kim, Haiying Chen, Xi Liu, Jia Zhou, Qiang Shen. Development of oridonin-based proteolysis-targeting chimera (PROTAC) degraders as effective breast cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 426.