RESUMO
Small molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αvß3 integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting of F-OH-Evo and improved the anti-tumor activities. Among them, compound 3c demonstrated the best selective inhibitory activity toward U87 cancer cells in vitro. It selectively enterd U87 cells by binding to αvß3 integrin, releasing the parent molecule under the dual response of ROS and GSH to exert inhibitory activity on topo I. The results highlight the potential of cRGD-conjugated prodrugs in targeted cancer therapy. This approach signifies a significant advancement in developing safer and more effective chemotherapy drugs, emphasizing the role of prodrug strategies in overcoming the limitations of traditional cancer treatments.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeos Cíclicos , Pró-Fármacos , Quinazolinas , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Integrina alfaVbeta3/metabolismo , Integrina alfaVbeta3/antagonistas & inibidores , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Relação Estrutura-Atividade , Quinazolinas/química , Quinazolinas/farmacologiaRESUMO
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer-PROTAC conjugation approach is developed to enhance tumor targeting and antitumor potency. Specifically, a smart prodrug is designed by conjugating "drugtamer" to a nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using a tumor microenvironment responsible linker. The "drugtamer" consists of fluorouridine nucleotide and DNA-like oligomer. Compared to NAMPT PROTAC and the combination of PROTAC + fluorouracil, the designed prodrug AS-2F-NP demonstrates superior tumor targeting, efficient cellular uptake, improved in vivo potency and reduced side effects. This study provides a promising strategy for the precise delivery of PROTAC and synergistic antitumor agents.
Assuntos
Antineoplásicos , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Humanos , Linhagem Celular Tumoral , Proteólise/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Modelos Animais de Doenças , Nicotinamida Fosforribosiltransferase/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Sinergismo FarmacológicoRESUMO
Nicotinamide adenine dinucleotide (NAD+ ) is an essential coenzyme with diverse biological functions in DNA synthesis. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme involved in NAD+ biosynthesis in mammals. We developed the first chemical tool for optical control of NAMPT and NAD+ in biological systems using photoswitchable proteolysis-targeting chimeras (PS-PROTACs). An NAMPT activator and dimethylpyrazolazobenzene photoswitch were used to design highly efficient PS-PROTACs, enabling up- and down-reversible regulation of NAMPT and NAD+ in a light-dependent manner and reducing the toxicity associated with inhibitor-based PS-PROTACs. PS-PROTAC was activated under 620â nm irradiation, realizing in vivo optical manipulation of antitumor activity, NAMPT, and NAD+ .
Assuntos
NAD , Nicotinamida Fosforribosiltransferase , Animais , Mamíferos , Quimera de Direcionamento de ProteóliseRESUMO
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Fotoquimioterapia , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Glipicanas/uso terapêutico , Peptídeos/farmacologia , Peptídeos/uso terapêuticoRESUMO
Proteolysis-targeting chimeras (PROTACs) have recently emerged as a promising technology for drug development. However, poor water solubility, limited tissue selectivity, and inadequate tumor penetration pose significant challenges for PROTAC-based therapies in cancer treatment. Herein, we developed an iRGD-PROTAC conjugation strategy utilizing tumor-penetrating cyclic peptide iRGD (CRGDK/RGPD/EC) to deliver PROTACs deep into breast cancer tissues. As a conceptual validation study, iRGD peptides were conjugated with a bromodomain-containing protein 4 (BRD4) PROTAC through a GSH-responsive linker. The resulting iRGD-PROTAC conjugate iPR showed enhanced water solubility, tumor-targeting capability, and penetration within tumor tissues, resulting in increased antibreast cancer efficacy in animal models and patient-derived organoids. This study demonstrates the advantages of combining iRGD and PROTACs in improving drug delivery and highlights the importance of tissue selectivity and penetration ability in PROTAC-based therapeutics.
Assuntos
Neoplasias da Mama , Animais , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Proteólise , Quimera de Direcionamento de Proteólise , Proteínas Nucleares , Linhagem Celular Tumoral , Fatores de Transcrição , Água , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo CelularRESUMO
[This corrects the article DOI: 10.3389/fchem.2022.840131.].
RESUMO
The identification of novel candidate molecules with the potential to revolutionize the treatment of breast cancer holds profound clinical significance. Macropin (Mac)-1, derived from the venom of wild bees, emerges as an auspicious therapeutic agent for combating breast cancers. Nevertheless, linear peptides have long grappled with the challenges of traversing cell membranes and succumbing to protease hydrolysis. To address this challenge, the present study employed hydrocarbon stapling modification to synthesize a range of stapled Mac-1 peptides, which were comprehensively evaluated for their chemical and biological properties. Significantly, Mac-1-sp4 exhibited a remarkable set of improvements, including enhanced helicity, proteolytic stability, cell membrane permeability, induction of cell apoptosis, in vivo antitumor activity, and inhibition of tubulin polymerization. This study explores the significant impact of the hydrocarbon stapling technique on the secondary structure, hydrolase stability, and biological activity of Mac-1, shedding light on its potential as a revolutionary and potent anti-breast cancer therapy. The findings establish a strong basis for the development of innovative and highly effective anti-tumor treatments.
Assuntos
Neoplasias , Peptídeos , Animais , Abelhas , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Peptídeo Hidrolases , Apoptose , Membrana Celular , HidrocarbonetosRESUMO
BACKGROUND: Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered. METHODS: A reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer. RESULTS: Luciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-ß/C-Raf/MAPK pathway by sandwiching into 14-3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo. CONCLUSIONS: In summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis.
Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Masculino , Humanos , Osteoclastos/metabolismo , Osteoclastos/patologia , Proteínas 14-3-3/metabolismo , Simulação de Acoplamento Molecular , Neoplasias Ósseas/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Heterostructures comprising lanthanide-doped upconversion nanoparticles (DUCNPs) and metal-organic frameworks (MOFs) are emerging as promising nanosystems for integrating medical diagnosis and treatment. Here, the DUCNP@Mn-MOF nanocarrier was developed, which showed good efficiency for loading and delivering a cytotoxic antitumor agent (3-F-10-OH-evodiamine, FOE). The combined advantages of the pH-responsive and peroxidase-like properties of Mn-MOF and the unique optical features of DUCNPs granted the DUCNP@Mn-MOF/FOE system synergistic chemodynamic and chemotherapeutic effects. The DUCNP@Mn-MOF nanocarrier effectively overcame the intrinsic limitations of FOE, such as its unfavorable physicochemical properties and limited in vivo potency. This complexed nanosystem was responsive to the tumor microenvironment and showed excellent tumor targeting capability. Thus, DUCNP@Mn-MOF/FOE exhibited highly selective and bioavailable drug delivery properties and is promising for cancer therapy. In a mouse breast cancer model, DUCNP@Mn-MOF/FOE inhibited tumor growth without significant toxicity. Therefore, the proposed nanosystem represents a promising theragnostic platform for multimodal combination diagnosis and therapy of tumors.
Assuntos
Antineoplásicos , Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Animais , Camundongos , Sistemas de Liberação de Medicamentos , Estruturas Metalorgânicas/química , Neoplasias/tratamento farmacológico , Nanopartículas/química , Microambiente TumoralRESUMO
Nicotinamide phosphoribosyltransferase (NAMPT) is identified as a promising target for cancer therapy. However, known NAMPT inhibitors are characterized by weak clinical efficacy and dose-dependent toxicity. There is an urgent need to develop new NAMPT intervention strategies. Using the proteolysis-targeting chimera (PROTAC) technology, we designed and synthesized a series of new von Hippel-Lindau (VHL)-recruiting NAMPT-targeting PROTACs. A highly potent NAMPT degrader (B3) was successfully identified, which displayed excellent degradation activity (DC50 < 0.17 nM, Dmax > 90%) and antiproliferative potency against A2780 cells (IC50 = 1.5 nM). PROTAC B3 induced NAMPT depletion in a concentration- and time-dependent manner through the ubiquitin-proteasome system. Particularly, PROTAC B3 achieved good plasma exposure levels via intravenous injection, gained potent tumor growth inhibition (TGI = 88.1%, 2 µM/kg) in the xenograft model, and demonstrated good biosafety without undesired toxicities. This study provides a highly potent VHL-recruiting NAMPT degrader for the treatment of ovarian cancer.
Assuntos
Neoplasias Ovarianas , Feminino , Humanos , Linhagem Celular Tumoral , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteóliseRESUMO
OBJECTIVES: Liver cancer stem cells (LCSCs) are regarded as the frequent cause of hepatocellular carcinoma (HCC) relapse and therapeutic resistance. The epithelial cell adhesion molecule (EpCAM) is one of the key biomarkers for LCSCs. EpCAM+ cells from HCC have been reported to display cancer stem cell-like (CSC-like) properties. Therefore, we aimed to verify the effect of MASM, a novel derivative of matrine, on CSC-like properties of EpCAM+ HCC cells. METHODS: EpCAM+ cells were isolated from Hep3B and Huh7 cells using the magnetic-activated cell sorting. The capacity for self-renewal and proliferation of EpCAM+ HCC cells was determined by the sphere-formation and cell counting kit 8 assays. After these cell populations were exposed to increasing concentrations of MASM, sphere formation, cell proliferation, apoptosis, resistance to chemotherapy and colony formation were evaluated, respectively. Moreover, the stemness-associated gene expression and underlying mechanisms were evaluated by quantitative real-time polymerase chain reaction and sphere-forming assay. RESULTS: MASM significantly inhibited proliferation without inducing apoptosis, down-regulated the expression of stemness-related genes, decreased the percentage of EpCAM+ HCC cells and up-regulated mature hepatocyte-related genes. Moreover, MASM suppressed the formation and reduced the size of not only primary spheroids but also subsequent spheroids. Additionally, our results showed that MASM inhibited the AKT/GSK3ß/ß-catenin signaling pathway. CONCLUSION: MASM treatment is effective against EpCAM+ cells and may be considered as a novel drug candidate in HCC therapy.
RESUMO
Proteolysis-targeting chimera (PROTAC) is emerging as a promising technology in targeted protein degradation and drug discovery. However, there is still a lack of effective chemical tools to real-time detect and track the protein degradation. Herein, the first fluorescent and theranostic PROTACs were designed for imaging the degradation of nicotinamide phosphoribosyltransferase (NAMPT) in living cells. Compound B4 was proven to be an environmentally sensitive fluorescent PROTAC, which efficiently degraded NAMPT (DC50 = 8.4 nM) and enabled the visualization of degradation in A2780 cells. As a theranostic agent, PROTAC B4 led to significant reduction of nicotinamide adenine dinucleotide (NAD+) and exerted potent antitumor activities both in vitro and in vivo. Collectively, this proof-of-concept study provides a new strategy for the real-time visualization of the process of protein degradation and the improvement of diagnosis and therapeutic efficacy of PROTACs.
Assuntos
Nicotinamida Fosforribosiltransferase , Quimera de Direcionamento de Proteólise , Feminino , Humanos , Linhagem Celular Tumoral/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/química , Neoplasias Ovarianas , Proteólise/efeitos dos fármacos , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologiaRESUMO
As a promising targeted drug delivery system, aptamer-drug conjugates (ApDCs) can specifically bind with cognate molecular targets for improving therapeutic efficacy and reducing drug toxicity. However, current ApDC strategies suffer from problems caused by the complicated synthesis, relatively high cost, low controllability of drug binding sites and loading ratio. To solve these difficulties, we have designed and synthesized an artificial pharmaceutical solid-phase module of Combretastatin A-4 (CA-4), in which an inactive ingredient was selected as bonding moiety to incorporate with solid phase functionalities. Through solid-phase synthesis technology, this module was automatically and efficiently conjugated with an aptamer at predesigned positions. Biological studies revealed that these ApDCs can not only maintain excellent specific recognition ability, but also possess definite cytotoxicity against tumor cells.
Assuntos
Aptâmeros de Nucleotídeos , Aptâmeros de Nucleotídeos/química , Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Técnicas de Síntese em Fase SólidaRESUMO
B1-Leu peptide is a structural optimization compound derived from the lysine- and phenylalanine-rich antimicrobial peptide Cathelicidin-BF. It has shown promising antibacterial and antitumor biological activity. However, linear peptides are not the best choice for novel drug development due to their poor pharmacokinetic properties. In this study, various all-hydrocarbon stapled B1-Leu derivatives were designed and synthesized. Their secondary structure, protease stability, and antitumor and hemolytic activities were also investigated to evaluate their clinical value for cancer therapy. Among them, B1-L-3 and B1-L-6 showed both damaging the tumor cell membrane stability and antitumor activity, showing that they are promising lead compounds for the development of novel cancer therapeutics.
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Pancreatic carcinoma (PC) has one of the highest mortality-to-incidence ratios of any solid tumor worldwide. Although KRAS mutation is commonly found in 95% of PCs, directly targeting KRAS remains to be a highly challenging task because of its lacking catalytic pockets where molecule inhibitors can bind with. Proteolysis-targeting chimeric (PROTAC) represents an effective approach for specific degradation of disease-causing proteins by hijacking the endogenous ubiquitin-proteasome system (UPS). Previously, we designed a first-in-class PROTAC induced PDEδ degrader (PIPD), which demonstrated improved anti-tumor efficacy against KRAS mutant malignancies. However, translating cellular degradative effects from bench to beside remains a highly challenging task because of PROTAC's poor penetration efficiency across target cytomembranes and non-targeting delivery induced undesired "off target" side-effects. Herein, a smart nano-drug delivery system (CM8988-PIPD) was successfully constructed by biomimetic strategy for targeted delivery of PIPD. The biomimetic nanoparticle showed well-defined regular spherical structure with an average particle size of approximately 124.8 nm. Cancer cytomembrane camouflage endows CM8988-PIPD with excellent in vivo serum stability, controlled drug release profile, favorable biocompatibility & immunocompatibility, and prominent targeting ability to homologous PC cells. Owing to these advantages, the smart DDS significantly enhanced PDEδ degrading efficacy, resulting in induced cellular apoptosis (more than 50% for both PC cells) and suppressed cell proliferation via the inhibition of RAS signaling. In vitro studies illustrated that CM8988-PIPD hold great potential for the treatment of PC, which merits further investigation in both pre-clinical and clinical investigations in the future.
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The development of KRAS-PDEδ protein-protein interaction (PPI) inhibitors is generally hampered by limited antitumor activity. Herein, the first hydrophobic tagging (HyT)-based PDEδ degraders were designed. Compound 17c efficiently bound to PDEδ and induced degradation of PDEδ in SW480 colon cancer cells. As compared with PDEδ inhibitor deltazinone, HyT-based degrader 17c exhibited improved antitumor activity toward KRAS mutant cancer cells. This study highlighted the potential of HyT as a valuable chemical tool for tumorigenic PDEδ knockdown, which could be developed into a promising strategy for antitumor drug discovery.
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Alyteserin-2a (ILGKLLSTAAGLLSNLNH2 ) is isolated from the skin exudates of midwife toad and has a wide range of biological applications. However, the use of alyteserin-2a as an antitumor agent is limited due to its structural flexibility. In this study, a series of stapled peptides were prepared through hydrocarbon stapling modification without destroying the key residues, and their chemical and biological properties were further evaluated for enhancing the application potential of alyteserin-2a in the field of antitumor drugs development. Among them, alyteserin-2a-Sp3 displayed significant improvement in helicity levels, protease resistance, and antitumor activity compared to that of the template peptide alyteserin-2a, indicating that alyteserin-2a-Sp3 had a potential to become a lead compound for the development of novel antitumor drugs. This study confirms the important effect of hydrocarbon stapling strategy on the secondary structure, hydrolase stability, and biological activity of alyteserin-2a.
Assuntos
Peptídeos Catiônicos Antimicrobianos , Antineoplásicos , Peptídeos/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/química , Antineoplásicos/farmacologia , Anuros , Hidrocarbonetos , Peptídeos/química , Estrutura Secundária de ProteínaRESUMO
Visible-light-driven sulfonylation/cyclization of N-methacryloyl-2-phenylbenzoimidazoles has been successfully developed. Using commercially available sulfonyl chloride as sulfonylation reagent, a wide range of sulfonylated benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-ones with potential antitumor activity were provided in acceptable to excellent yields. This method has the advantages of mild reaction conditions and outstanding functional group tolerance, and provides a new strategy for the development of potential antitumor lead compounds.
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The dose-related adverse effects of MDM2âP53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2âP53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment.
RESUMO
Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs.