Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer.

Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.

Baicalin-2-ethoxyethyl ester alleviates gentamicin-induced acute kidney injury via NF-κB signaling pathway.

Drug nephrotoxicity has high fatality rates and complications. To study this conditional, traditionally, Gentamicin (GM) is used to induce acute injury and establish a nephrotic syndrome model. Baicalin, a flavonoid derived from baicalin with potent anti-inflammatory and antioxidant activity, has been used to treat various inflammatory diseases. This study aims to investigate the process of baicalin-2-ethoxyethyl ester (BAE) synthesis and its therapeutic effect on GM-induced acute kidney injury (AKI). Briefly, baicalin was processed by various reactions to yield BAE. A GM-induced AKI model was established for in vivo evaluation of the protective effect and mechanism of BAE. The results indicated that BAE reduced serum creatinine and urea nitrogen levels and improved pathological alterations, inflammatory responses, and oxidative stress in renal tissues. Furthermore, it was revealed that BAE might exert anti-inflammatory and anti-oxidative responses during AKI via the NF-κB signaling pathway regulation. The findings imply that BAE has a protective impact on the kidneys and might serve as a potent medicine for treating renal damage.

Baicalin - 2- ethoxyethyl ester alleviates renal fibrosis by inhibiting PI3K/AKT/NF-κB signaling pathway.

With the increasing incidence of chronic kidney disease (CKD), the development of safe and effective anti-renal fibrosis drugs is particularly urgent. Recently, Baicalin has been considered to have a renal protective effect, but its bioavailability is too low. Therefore, we synthesized baicalin-2-ethoxyethyl ester (BAE) by esterification of baicalin. We hope that this experiment will demonstrate the anti-renal fibrosis effect of BAE and explain its molecular mechanism. In this study, the chronic kidney injury model of SD rats was established by 5/6 nephrectomy, and BAE was given for 28 days. The results showed that after BAE treatment, the serum creatinine and urea nitrogen levels decreased significantly, and the pathological changes in kidneys were improved. In addition, RNA-seq analysis showed that the mechanism of BAE in relieving renal fibrosis was related to the ECM receptor, PI3K/AKT signaling pathway, and inflammatory reaction. The western blotting analysis confirmed that BAE could inhibit the expression of α-SMA, TGF-ß1, p-PI3K, p-AKT, p-IκBα, and NF-κB p65. We found that BAE can inhibit the inflammatory reaction and promote the degradation of the extracellular matrix by inhibiting the activation of the PI3K/AKT/NF-κB pathway, thus alleviating the symptoms of renal fibrosis in 5/6Nx rats, which revealed BAE was a potential compound to relieve renal fibrosis effect.

Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation.

Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.

Fragment-based design, synthesis and biological evaluation of theophylline derivatives as ATAD2 inhibitors in BT-549 cells.

ATPase family AAA domain-containing protein 2 (ATAD2) has been emerging as a hot anti-cancer drugable target due to its oncogenic epigenetic modification closely associated with cancer cells proliferation, apoptosis, migration and drug resistance. In this study, we design a series of theophylline derivatives as novel ATAD2 inhibitors through fragment-based screening and scaffold growth strategy. A novel potent ATAD2 inhibitor (compound 19f) is discovered with an IC50 value of 0.27 µM against ATAD2, which adopts a combination of classic and atypical binding mode. Additionally, compound 19f could impede ATAD2 activity and c-Myc activation, induced significant apoptosis, and illustrated an anti-migration effect in BT-549 cells. Collectively, these results provide new enlightenment for the development of novel potent ATAD2 inhibitors for triple-negative breast cancer (TNBC) treatment.

Identification of a novel PAK1/HDAC6 dual inhibitor ZMF-23 that triggers tubulin-stathmin regulated cell death in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most poorly treated subtype of breast cancer, and targeting the heterogeneity of TNBC has emerged as a fascinating therapeutic strategy. In this study, we propose for the first time that dual-targeting PAK1 and HDAC6 is a promising novel strategy for TNBC treatment due to their essential roles in the regulation of energy metabolism and epigenetic modification. We discovered a novel dual-targeting PAK1/HDAC6 inhibitor, 6 - (2-(cyclopropylamino) - 6 - (2,4-dichlorophenyl) - 7 - oxopyrido [2,3-d] pyrimidin - 8 (7H) -yl) - N-hydroxyhexanamide (ZMF-23), which presented profound inhibitory activity against PAK1 and HDAC6 and robust antiproliferative potency in MDA-MB-231 cells. In addition, SPR and CETSA assay demonstrated the targeted binding of ZMF-23 with PAK1/HDAC6. Mechanically, ZMF-23 strongly inhibited the cellular PAK1 and HDAC6 activity, impeded PAK1 and HDAC6 regulated aerobic glycolysis and migration. By RNA-seq analysis, ZMF-23 was found to induce TNF-α-regulated necroptosis, which further enhanced apoptosis. Additionally, ZMF-23 triggered PAK1-tubulin/HDAC6-Stathmin regulated microtubule structure changes, which further induced the G2/M cycle arrest. Moreover, prominent anti-proliferative effect of ZMF-23 was confirmed in the TNBC xenograft zebrafish and mouse model via PAK1 and HDAC6 inhibition. Collectively, ZMF-23 is a novel dual PAK1/HDAC6 inhibitor with TNBC treatment potential.

Unraveling the complexity of histone-arginine methyltransferase CARM1 in cancer: From underlying mechanisms to targeted therapeutics.

Coactivator-associated arginine methyltransferase 1 (CARM1), a type I protein arginine methyltransferase (PRMT), has been widely reported to catalyze arginine methylation of histone and non-histone substrates, which is closely associated with the occurrence and progression of cancer. Recently, accumulating studies have demonstrated the oncogenic role of CARM1 in many types of human cancers. More importantly, CARM1 has been emerging as an attractive therapeutic target for discovery of new candidate anti-tumor drugs. Therefore, in this review, we summarize the molecular structure of CARM1 and its key regulatory pathways, as well as further discuss the rapid progress in better understanding of the oncogenic functions of CARM1. Moreover, we further demonstrate several representative targeted CARM1 inhibitors, especially focusing on demonstrating their designing strategies and potential therapeutic applications. Together, these inspiring findings would shed new light on elucidating the underlying mechanisms of CARM1 and provide a clue on discovery of more potent and selective CARM1 inhibitors for the future targeted cancer therapy.

Dual-target inhibitors of PARP1 in cancer therapy: A drug discovery perspective.

Poly (ADP-ribose) polymerase 1 (PARP1), a key enzyme in DNA repair, has emerged as a promising anticancer druggable target. An increasing number of PARP1 inhibitors have been discovered to treat cancer, most notably those characterized by BRCA1/2 mutations. Although PARP1 inhibitors have achieved great clinical success, their cytotoxicity, development of drug resistance, and restriction of indication have weakened their clinical therapeutic effects. To address these issues, dual PARP1 inhibitors have been documented as a promising strategy. Here, we review recent progress in the development of dual PARP1 inhibitors, summarize the different designs of dual-target inhibitors, and introduce their antitumor pharmacology, shedding light on the discovery of dual PARP1 inhibitors for cancer treatment.

ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target.

ATPase family AAA domain-containing protein 2 (ATAD2) has been widely reported to be a new emerging oncogene that is closely associated with epigenetic modifications in human cancers. As a coactivator of transcription factors, ATAD2 can participate in epigenetic modifications and regulate the expression of downstream oncogenes or tumor suppressors, which may be supported by the enhancer of zeste homologue 2. Moreover, the dominant structure (AAA + ATPase and bromine domains) can make ATAD2 a potential therapeutic target in cancer, and some relevant small-molecule inhibitors, such as GSK8814 and AZ13824374, have also been discovered. Thus, in this review, we focus on summarizing the structural features and biological functions of ATAD2 from an epigenetic modulator to a cancer therapeutic target, and further discuss the existing small-molecule inhibitors targeting ATAD2 to improve potential cancer therapy. Together, these inspiring findings would shed new light on ATAD2 as a promising druggable target in cancer and provide a clue on the development of candidate anticancer drugs.

Total glycosides of Rhodiola rosea L. attenuate LPS-induced acute lung injury by inhibiting TLR4/NF-κB pathway.

Acute lung injury (ALI) is a common respiratory disease in clinics, which is characterized by alveolar-capillary membrane loss, plasma protein leakage, pulmonary edema, massive neutrophil infiltration, and the release of proinflammatory cytokines and mediators. Rhodiola rosea L. an adaptogenic plant rich in phenylethanoloids, phenylpropanoids, monoterpenes, has anti-inflammatory and antioxidant effects. We hope to verify the relieving effect of total glycosides of Rhodiola rosea L. (RTG) on ALI in mice and clarify its mechanism through this study. In this study, we identified the effect and mechanism of RTG on ALI through LPS-induced ALI mice. After RTG treatment, the pathological structure of lung tissue in ALI mice induced by LPS was significantly improved, and the infiltration of inflammatory cells was reduced. In addition, RTG reduced the production of IL-6, IL-1ß, and TNF-α in the serum of ALI mice and reduced the content or activity of MPO, T-SOD, GSH, and MDA in lung tissue. RNAseq analysis showed that RTG ameliorated LPS-induced ALI through anti-inflammatory, reduced immune response, and anti-apoptotic activities. The western blotting analysis confirmed that RTG could down-regulate the expression levels of TLR4, MyD88, NF-κB p65, and p-IκBα/IκBα. These results suggest that RTG can attenuate LPS-induced ALI through antioxidants and inhibition of the TLR4/NF-κB pathway.

Near-infrared AIE-active phosphorescent iridium(III) complex for mitochondria-targeted photodynamic therapy.

Mitochondria-targeted photodynamic therapy (PDT) has recently been recognized as a promising strategy for effective cancer treatment. In this work, a mitochondria-targeted near-infrared (NIR) aggregation-induced emission (AIE)-active phosphorescent Ir(III) complex (Ir1) is reported with highly favourable mitochondria-targeted bioimaging and cancer PDT properties. Complex Ir1 has strong absorption in the visible light region (∼500 nm) and can effectively produce singlet oxygen (1O2) under green light (525 nm) irradiation. It preferentially accumulates in the mitochondria of human breast cancer MDA-MB-231 cells as revealed by colocalization analysis. Complex Ir1 displays high phototoxicity toward human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. Complex Ir1 induces reactive oxygen species (ROS) production, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in MDA-MB-231 cells upon photoirradiation, leading to apoptotic cell death. The favorable PDT performance of Ir1in vivo has been further demonstrated in tumour-bearing mice. Together, the results suggest that Ir1 is a promising photosensitizer for mitochondria-targeted imaging and cancer phototherapy.

Identification of LRRK2 Inhibitors through Computational Drug Repurposing.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects more than ten million people worldwide. However, the current PD treatments are still limited and alternative treatment strategies are urgently required. Leucine-rich repeat kinase 2 (LRRK2) has been recognized as a promising target for PD treatment. However, there are no approved LRRK2 inhibitors on the market. To rapidly identify potential drug repurposing candidates that inhibit LRRK2 kinase, we report a structure-based drug repurposing workflow that combines molecular docking, recursive partitioning model, molecular dynamics (MD) simulation, and molecular mechanics-generalized Born surface area (MM-GBSA) calculation. Thirteen compounds screened from our drug repurposing workflow were further evaluated through the experiment. The experimental results showed six drugs (Abivertinib, Aumolertinib, Encorafenib, Bosutinib, Rilzabrutinib, and Mobocertinib) with IC50 less than 5 µM that were identified as potential LRRK2 kinase inhibitors. The most potent compound Abivertinib showed potent inhibitions with IC50 toward G2019S mutation and wild-type LRRK2 of 410.3 nM and 177.0 nM, respectively. Our combination screening strategy had a 53% hit rate in this repurposing task. MD simulations and MM-GBSA free energy analysis further revealed the atomic binding mechanism between the identified drugs and G2019S LRRK2. In summary, the results showed that our drug repurposing workflow could be used to identify potent compounds for LRRK2. The potent inhibitors discovered in our work can be a starting point to develop more effective LRRK2 inhibitors.

Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression.

A primary strategy employed in cancer therapy is the inhibition of topoisomerase II (Topo II), implicated in cell survival. However, side effects and adverse reactions restrict the utilization of Topo II inhibitors. Thus, investigations focus on the discovery of novel compounds that are capable of inhibiting the Topo II enzyme and feature safer toxicological profiles. Herein, we upgrade an old antibiotic chrysomycin A from Streptomyces sp. 891 as a compelling Topo II enzyme inhibitor. Our results show that chrysomycin A is a new chemical entity. Notably, chrysomycin A targets the DNA-unwinding enzyme Topo II with an efficient binding potency and a significant inhibition of intracellular enzyme levels. Intriguingly, chrysomycin A kills KRAS-mutant lung adenocarcinoma cells and is negligible cytotoxic to normal cells at the cellular level, thus indicating a capability of potential treatment. Furthermore, mechanism studies demonstrate that chrysomycin A inhibits the Topo II enzyme and stimulates the accumulation of reactive oxygen species, thereby inducing DNA damage-mediated cancer cell apoptosis. Importantly, chrysomycin A exhibits excellent control of cancer progression and excellent safety in tumor-bearing models. Our results provide a chemical scaffold for the synthesis of new types of Topo II inhibitors and reveal a novel target for chrysomycin A to meet its further application.

The Amomum tsao-ko Essential Oils Inhibited Inflammation and Apoptosis through p38/JNK MAPK Signaling Pathway and Alleviated Gentamicin-Induced Acute Kidney Injury.

The clinical application of gentamicin may lead to acute kidney injury (AKI), and the nephrotoxicity of gentamicin is related to the pathological mechanism of several oxidative and inflammatory cytokines. Plant-derived essential oils have good anti-inflammatory and antioxidant properties. This study aimed to clarify the protective effect of Amomum tsao-ko essential oils (AOs) on gentamicin-induced AKI in rats and its possible mechanism. The rat AKI model was induced by intraperitoneal injection of gentamicin. After 14 days of oral AO treatment, the renal function and pathological changes of the kidney tissues were evaluated, and the level of kidney tissue oxidative stress was detected. The content of inflammatory cytokines was measured by ELISA. The expression of ERK1/2, JNK1/2, p38, NF-κB, caspase-3, and Bax/Bcl-2 proteins were estimated by Western blot analysis. The results showed that taking AO reduced the contents of serum urea and creatinine in AKI rats and improve the pathological changes and oxidative stress of the kidney tissue in rats. At the same time, AO reduced inflammation and apoptosis during AKI by regulating the MAPK pathway. The data show that AO has a protective effect on the kidneys and may be a potential drug for treating kidney injury.

A practical strategy to develop isoform-selective near-infrared fluorescent probes for human cytochrome P450 enzymes.

Currently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system. In the second stage of our filtering approach, these candidates were further screened using reverse protein-ligand docking to effectively determine CYP isoenzyme-specific probe(s). Using our double-filtering approach, probes S9 and S10 were successfully developed for the real-time and selective detection of CYP2C9 and CYP2J2, respectively, to facilitate high-throughput screening and assessment of CYP2C9-mediated clinical drug interaction risks and CYP2J2-associated disease diagnosis. These observations suggest that our strategy could be used to develop the isoform-specific probes for CYPs.

Three new tyrosol derivatives from Huangjing wine.

Phytochemical investigation on the concentrate of Huangjing wine, resulted in the isolation of three new tyrosol derivatives 4'''-hydroxyphenethyl 2-(R)-hydroxy-3-phenylpropionate (1), 4'''-hydroxyphenethyl(4'-hydroxy-3'-methoxyphenyl)propionate (2) and 4''-hydroxyphenethyl ethyl succinate (3), together with 5 known compounds, ferulic acid (4), L-phenyllactic acid (5), hydroxytyrosol (6), dihydroferulic acid (7), cyclo(L-Pro-D-Tyr) (8). Their structures were elucidated using spectroscopic analysis and by comparison with the literature data. All compounds displayed antioxidant effect in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. Among them, the new compound 2 exhibited obvious antioxidant effect, and new compounds 1 and 3 exhibited medium antioxidant effect.

Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects.

Background: The prevalence of hyperuricemia is considered high worldwide. Hyperuricemia occurs due to decreased excretion of uric acid, increased synthesis of uric acid, or a combination of both mechanisms. There is growing evidence that hyperuricemia is associated with a decline of renal function. Purpose: This study is aimed at investigating the effects of the novel compound on lowering the serum uric acid level and alleviating renal inflammation induced by high uric acid in hyperuricemic mice. Methods: Hyperuricemic mice model was induced by potassium oxonate and used to evaluate the effects of the novel compound named FxUD. Enzyme-linked immunosorbent assay was used to detect the related biochemical markers. Hematoxylin-eosin (HE) staining was applied to observe pathological changes. The mRNA expression levels were tested by qRT-PCR. The protein levels were determined by Western blot. In parallel, human proximal renal tubular epithelial cells (HK-2) derived from normal kidney was used to further validate the anti-inflammatory effects in vitro. Results: FxUD administration significantly decreased serum uric acid levels, restored the kidney function parameters, and improved the renal pathological injury. Meanwhile, treatment with FxUD effectively inhibited serum and liver xanthine oxidase (XOD) levels. Reversed expression alterations of renal inflammatory cytokines, urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were observed in hyperuricemic mice. Western blot results illustrated FxUD down-regulated protein levels of inflammasome components. Further studies showed that FxUD inhibited the activation of NF-κB signaling pathway in the kidney of hyperuricemic mice. In parallel, the anti-inflammatory effect of FxUD was also confirmed in HK-2. Conclusion: Our study reveals that FxUD exhibits the anti-hyperuricemic and anti-inflammatory effects through regulating hepatic XOD and renal urate reabsorption transporters, and suppressing NF-κB/NLRP3 pathway in hyperuricemia. The results provide the evidence that FxUD may be potential for the treatment of hyperuricemia with kidney inflammation.

Atorvastatin Ester Regulates Lipid Metabolism in Hyperlipidemia Rats via the PPAR-signaling Pathway and HMGCR Expression in the Liver.

Atorvastatin ester (Ate) is a structural trim of atorvastatin that can regulate hyperlipidemia. The purpose of this study was to evaluate the lipid-lowering effect of Ate. Male Sprague Dawley (SD) rats were fed a high-fat diet for seven months and used as a hyperlipidemia model. The lipid level and liver function of the hyperlipidemia rats were studied by the levels of TG, TC, LDL, HDL, ALT, and AST in serum after intragastric administration with different doses of Ate. HE staining was used to observe the pathological changes of the rat liver and gastrocnemius muscle. The lipid deposits in the liver of rats were observed by staining with ORO. The genes in the rat liver were sequenced by RNA-sequencing. The results of the RNA-sequencing were further examined by qRT-PCR and western blotting. Biochemical test results indicated that Ate could obviously improve the metabolic disorder and reduce both the ALT and AST levels in serum of the hyperlipidemia rats. Pathological results showed that Ate could improve HFD-induced lipid deposition and had no muscle toxicity. The RNA-sequencing results suggested that Ate affected liver lipid metabolism and cholesterol, metabolism in the hyperlipidemia-model rats may vary via the PPAR-signaling pathway. The western blotting and qRT-PCR results demonstrated the Ate-regulated lipid metabolism in the hyperlipidemia model through the PPAR-signaling pathway and HMGCR expression. In brief, Ate can significantly regulate the blood lipid level of the model rats, which may be achieved by regulating the PPAR-signaling pathway and HMGCR gene expression.

A NIR fluorescent probe for fatty acid amide hydrolase bioimaging and its application in development of inhibitors.

Fatty acid amide hydrolase (FAAH) is primarily responsible for the inactivation of fatty acid ethanolamide (FAE) and is involved in a variety of biological functions related to diseases of the nervous system. Herein, we developed a highly selective and sensitive FAAH-activated near-infrared fluorescent probe named DAND and achieved the real-time detection and imaging of FAAH activity in complex biosystems. Moreover, a visual high-throughput screening method was established using DAND, piperine was identified as a novel inhibitor of FAAH. Based on the interaction of piperine with FAAH, a more potent FAAH inhibitor (11f) was designed and synthesized which possessed an IC50 value of 0.65 µM. Furthermore, 11f could attenuate the liposaccharide (LPS)-induced activation of BV2 cells, exhibiting an excellent anti-inflammatory activity. These results indicated that DAND could be used as a promising molecular tool for exploring FAAH activity and for rapidly screening potential FAAH inhibitors. In addition, piperine and its derivatives could serve as potential candidate drugs for the treatment of neurodegenerative diseases in the future.

Design, synthesis and biological evaluation of dual mTOR/HDAC6 inhibitors in MDA-MB-231 cells.

The excessive activation of histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) signaling promotes tumor growth and progression. We proposed that dual targeting mTOR and HDAC inhibitors is a promising strategy for triple negative breast cancer (TNBC) treatment. In this study, a series of dual mTOR/HDAC6 inhibitors were designed and synthesized by structure-based strategy. 10g was documented to be a potent dual mTOR/HDAC6 inhibitor with IC50 value of 133.7 nM against mTOR and 56 nM against HDAC6, presenting mediate antiproliferative activity in TNBC cells. Furthermore, we predicted the binding mode of 10g and mTOR/HDAC6 by molecule docking. In addition, 10g was documented to induce significant autophagy, apoptosis and suppress migration in MDA-MB-231 cells. Collectively, these findings revealed that 10g is a novel potent dual mTOR/HDAC6 inhibitor, which provides promising rationale for the combination of dual mTOR/HDAC6 inhibitors for TNBC treatment.