Malignant glioma (MG), a highly aggressive tumor in the central nervous system (CNS), is marked by rapid cell proliferation, high invasiveness, severe infiltration, indistinct tumor margins and significant heterogeneity [1,2]. Current treatment for MG involves surgical resection, with subsequent radiotherapy and chemotherapy [3]. Nonetheless, therapeutic effects of these approaches are limited, with a median survival time of only 12–15 months for MG patients [4]. Although immunomodulatory therapies are being explored, the efficacy and safety profiles remain under investigation [5]. Therefore, developing novel compounds that exhibit effectively anti-MG activity is paramount.

In recent years, Chinese herbal medicines have emerged as a research hotspot in anti-tumor studies due to their multi-target effects, low toxicity, and synergistic therapeutic enhancement [6]. Elephantopus scaber (E. scaber), belonging to the family Asteraceae, is widely used in Chinese medicine. A decoction made from the whole plant is administered orally in the treatment of hepatitis [7]. Besides, a paste prepared from E. scaber roots is usually applied around the ear as a remedy for headaches [8]. Moreover, E. scaber, in conjunction with other medicinal herbs, has been utilized in Ayurvedic medicine for the treatment of neoplasms [9]. E. scaber extract and its fractions exhibited significant inhibitory effects on colorectal cells [10]. The main bioactive ingredient of E. scaber is sesquiterpene lactones (SL), known for their diverse biological activities and have garnered significant research interest [10,11]. SLs, such as costunolide [12], helenalin [13], micheliolide [14], and alantolactone [15], generating a great deal of research interest, might be promising candidates to discover new anti-cancer drugs [16]. Notably, the SL-derived agent ACT001 (Fig. 1) has been successfully applied on treatment of MG in clinical trials [17]. Therefore, developing SL derivatives for MG therapy holds great potential.

Activity-Based Protein Profiling (ABPP) is a chemical proteomics methodology that utilizes rationally designed activity-based probes targeting specific enzyme active sites to achieve highly specific labeling, enrichment, and identification of functionally active proteins [18]. Natural products serve as a significant source for drug development, though the pharmacological mechanisms underlying many of them are not fully elucidated [19]. In previous studies, the application of ABPP technology coupled with mass spectrometry analysis has successfully identified cellular targets of natural products, thereby providing certain natural products interacting with specific enzymes or proteins to affect intracellular signaling pathways [20,21]. This approach has offered molecular-level evidence to elucidate the pharmacological effects of natural products.

Recently, our research team has extensively investigated the advancement of SL natural products from E. scaber and their analogs as potent anticancer agents [22,23]. Scaberol C (SC), a germacrane-type SL originally isolated from E. scaber, has been produced in large quantities from an E. scaber extract [24]. Our previous work demonstrated that chemical modifications at C6–OH of SC can enhance its anti-cancer properties [25]. Herein, sesquiterpene lactones were synthesized based on SC and ISC as part of our research efforts in anti-cancer drug discovery. After screening the in vitro anti-MG activity, a potent compound 1e displayed broad-spectrum inhibitory activity against U87, U251 and T98G cells. We subsequently determined the effect of 1e on proliferation, metastasis and related mechanisms of MG cells. Furthermore, the in vivo anti-MG efficacy of 1e was further evaluated in mice. In parallel, we designed and synthesized probes to identify potential targets using ABPP. Finally, the pharmacokinetic parameters of 1e were also investigated to offer more insights into its function.