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[Display omitted] • Design, synthesis and antitumor evaluation of biotin-PEG4‑diarylidenyl piperidone prodrugs. • In vitro and In vivo antitumor activity screening for prodrugs 3a and 3b. • 3a and 3b released their original drugs DAP-F and DAP-NO 2 in nude mice. • DAP-F , DAP-NO 2 , 3a and 3b targeted STAT3 inhibition. • 3a and 3b interacted with SH2-binding domain, while DAP-F and DAP-NO 2 interacted with DNA-binding domain. Two biotin-polyethylene glycol (PEG)4‑diarylidenyl piperidone (DAP) prodrugs, compounds 3a and 3b , were designed as antineoplastic agents and synthesized by coupling biotin to bifluoro- and binitro-substituted DAP derivatives (DAP-F and DAP-NO 2) through a PEG4 linker, respectively. The results of the MTT (3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di- phenytetrazoliumromide) assay and a SW480 xenograft model identified compounds 3a and 3b as candidate antitumor agents with good efficacy, limited toxicity, and low resistance, as compared to the original drugs (DAP-F and DAP-NO 2), cisplatin, and doxorubicin (dox). The results of a preliminary pharmacokinetic study showed that compounds 3a and 3b slowly released their original drug DAP-F and DAP-NO 2 within 12 h after intraperitoneal injection, respectively. Western blot analysis and computer docking simulations indicated that DAP-F , DAP-NO 2 , and compounds 3a and 3b were indeed inhibitors of signal transducer and activator of transcription 3 (STAT3) and the antitumor effects of compounds 3a and 3b were exerted by sequentially interacting with the SH2-binding domain followed by the DNA-binding domain after releasing the original drugs DAP-F and DAP-NO 2 , respectively. These results suggest that the targeted prodrug model led to good antitumor efficacy with reduced toxicity, while a dual STAT3-binding model may promote antitumor efficacy and resistance. [ABSTRACT FROM AUTHOR]