Aug 2026· European journal of medicinal chemistry· Vol 319, pp.
119220
· 0 citations· 51 references
Medicine
TL;DR
In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss.
Abstract
Peroxiredoxin 3 (PRDX3), located in mitochondria, plays a crucial catalytic role in maintaining mitochondrial redox homeostasis and represents a promising target for antitumor drug development. Celastrol is a natural inhibitor of PRDX3; however, it suffers from poor subtype selectivity and high toxicity. In this study, celastrol was used as a lead compound for structural optimization. First, we demonstrated that introducing a triphenylphosphine (TPP) group enables mitochondrial targeting and reduces cytotoxicity. Subsequently, the TPP moiety was exploited as a privileged fragment for further optimization. After two rounds of structural modification, compound 10d was obtained, exhibiting the best antiproliferative activity. Its key structural features include a TPP group attached at the C-3 position and an ethylamine fragment linked at the C-20 position. Compound 10d showed an IC50 value of 0.64 μM against H1975 cells, approximately 3-fold more potent than celastrol. Mechanistic studies revealed that 10d binds to PRDX3 with high affinity (Kd = 0.514 μM), about 17-fold higher than that of celastrol (Kd = 8.56 μM). Furthermore, 10d downregulated the downstream NF-κB and VEGF signaling pathways of PRDX3, effectively suppressing migration and invasion of H1975 cells. In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss. In summary, this study successfully developed a highly effective and safe mitochondrially targeted PRDX3 inhibitor, providing a valuable lead compound for the development of innovative drugs targeting tumor redox metabolism.
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
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Phenotypic drug discovery enables the identification of compounds with novel mechanisms of action and context-dependent biological activities that may not emerge from target-based approaches. Through high-content phenotypic screening, we identified the (E)-6-(2-((1H-indol-3-yl)methylene)hydrazineyl)-N,N-diethylpyrimidin-4-amine (IMHDPA) scaffold as a potent and highly selective inhibitor of HeLa cell proliferation. To further explore this scaffold, a library of 70 analogues was synthesized, and structure-activity relationship studies revealed stringent structural requirements for maintaining cellular potency and selectivity. Among them, compound 39 emerged as the most active derivative, exhibiting a GI50 value of 2.96 nM against HeLa cells and an exceptional selectivity index exceeding 16,000-fold across a panel of 15 cell lines. Compound 39 suppressed colony formation, migration, invasion, and spheroid growth, while inducing pronounced morphological alterations in HeLa cells. Mechanistic investigations indicated that its antiproliferative activity was associated with autophagy activation rather than apoptosis, necrosis, ferroptosis, or reactive oxygen species accumulation. Integrated transcriptomic and proteomic analyses implicated perturbation of cholesterol metabolism and inhibition of mTORC1 signaling as potential upstream events linked to autophagy induction. Collectively, these findings establish IMHDPA derivatives as promising chemical probes for investigating the molecular basis of context-dependent autophagy-associated cytotoxicity and support future efforts aimed at elucidating the molecular determinants underlying this selective phenotype.
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