Minnelide

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.