RESUMEN
Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA-PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC50 value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.
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Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Animales , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Simulación del Acoplamiento Molecular , Ratones Desnudos , Pez Cebra/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Relación Estructura-Actividad , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed AKT phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Inhibidores de Histona Desacetilasas/química , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas/metabolismo , Proliferación Celular , Antineoplásicos/química , Relación Estructura-Actividad , Leucemia Mieloide Aguda/tratamiento farmacológico , Zinc/farmacología , ApoptosisRESUMEN
Phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer and has become a key target for cancer drug development. Based on a 4-methyl quinazoline scaffold, we designed and synthesized a novel series of bivalent PI3K inhibitors with different linker lengths and types. Bivalent PI3K inhibitor 27 demonstrates improved PI3K potency and antiproliferative cell activity, relative to the corresponding monovalent inhibitor 11. Compound 27 also significantly blocks the PI3K signal pathway, induces cell cycle arrest in G1 phase, and inhibits colony formation and cell migration. Furthermore, compound 27 shows dose-dependent anticancer efficacies in a HGC-27 xenograft mice model. Overall, this work provides a possible strategy to discover novel PI3K inhibitors for the treatment of cancers.
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Neoplasias , Fosfatidilinositol 3-Quinasas , Humanos , Animales , Ratones , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa , Movimiento Celular , Modelos Animales de Enfermedad , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacologíaRESUMEN
A novel photocaged PI3K inhibitor 2 was designed and synthesized by introducing a cascade photocaging group to block its key interaction with the kinase. Upon UV light irradiation, the photocaged compound released a highly potent PI3K inhibitor to recover its anticancer properties and a fluorescent dye for real-time reporting of drug release, providing a new approach for studying the PI3K signaling transduction pathway as well as developing precisely controlled cancer therapeutics.
RESUMEN
Microtubule-targeting agents are widely used as active anticancer drugs. However, drug resistance always emerges after their long-term use, especially in the case of paclitaxel, which is the cornerstone of all subtypes of breast cancer treatment. Hence, the development of novel agents to overcome this resistance is vital. This study reports on a novel, potent, and orally bioavailable tubulin inhibitor called S-72 and evaluated its preclinical efficacy in combating paclitaxel resistance in breast cancer and the molecular mechanisms behind it. We found that S-72 suppresses the proliferation, invasion and migration of paclitaxel-resistant breast cancer cells in vitro and displays desirable antitumor activities against xenografts in vivo. As a characterized tubulin inhibitor, S-72 typically inhibits tubulin polymerization and further triggers mitosis-phase cell cycle arrest and cell apoptosis, in addition to suppressing STAT3 signaling. Further studies showed that STING signaling is involved in paclitaxel resistance, and S-72 blocks STING activation in paclitaxel-resistant breast cancer cells. This effect further restores multipolar spindle formation and causes deadly chromosomal instability in cells. Our study offers a promising novel microtubule-destabilizing agent for paclitaxel-resistant breast cancer treatment as well as a potential strategy that can be used to improve paclitaxel sensitivity.
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Targeting the colchicine binding site on tubulin is a promising strategy to develop cancer therapeutics. Herein, we describe our systematic structure-activity relationship studies of benzamide derivatives that lead to an identification of a potent and orally active tubulin inhibitor 48, which occupied all three zones of the colchicine binding site in the X-ray co-crystal structure, inhibited tubulin polymerization, promoted mitotic blockade and apoptosis, and exhibited significant antiproliferative activities against various cancer cell lines. Compound 48 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacies, and acceptable safety profiles. Furthermore, 48 overcame drug resistance in the paclitaxel-resistant A549 xenograft model. Collectively, 48 has been advanced into further preclinical evaluation for the development of next-generation microtubule-targeting drugs.
Asunto(s)
Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacología , Moduladores de Tubulina/uso terapéutico , Moduladores de Tubulina/química , Colchicina/metabolismo , Tubulina (Proteína)/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Línea Celular Tumoral , Sitios de Unión , Relación Estructura-Actividad , Proliferación Celular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Light has been used increasingly as an external stimulus in drug design. Herein, we report a novel photoswitchable azo-PI3K inhibitor, which bears an azobenzene moiety and can be efficiently converted between trans and cis configuration with changes of anticancer activity upon different light irradiation. Its photochemical properties were characterized by UV, LC-MS and NMR techniques. In biological assessment, trans and cis isomers of the azo-PI3K inhibitor exhibited differential anticancer activity in inhibition of PI3K pathway, cell migratory ability, and colony formation and can be switched at a cellular level upon light irradiation. Moreover, both isomers of the azo-PI3K inhibitor significantly inhibited tumor growth in a zebrafish xenograft model. Together, this photoswitchable azo-PI3K inhibitor may be useful as a valuable tool compound for studying the PI3K pathway and further optimization toward optically-controlled anticancer activity.
Asunto(s)
Fosfatidilinositol 3-Quinasas , Procesos Fotoquímicos , Animales , Compuestos Azo/química , Compuestos Azo/farmacología , Humanos , Isomerismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Pez CebraRESUMEN
The synergistic anti-tumor effect by simultaneous inhibitions of PI3K and HDAC has been verified to provide the rationality of PI3K/HDAC dual inhibitors for cancer treatment. Notably, the outstanding effect of PI3K/HDAC dual inhibitors against DLBCL has been paid much attention, especially for RR-DLBCL. Our previously reported 4-methylquinazoine scaffold based PI3K/HDAC dual inhibitors could suppress the growth of solid tumors and hematologic malignancies both in vitro and in vivo, validating the potential as new therapeutic agents for cancer. In this research, we further investigated the anti-tumor activity of one of our compounds against DLBCL cell lines and in vivo zebrafish xenograft model as well as the underlying mechanism, hoping to provide a novel therapeutic agent for treating DLBCL.
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Inhibidores de Histona Desacetilasas , Linfoma de Células B Grandes Difuso , Animales , Apoptosis , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Pez CebraRESUMEN
Phosphoinositide 3-kinase δ (PI3Kδ) plays a critical role in B lymphocyte (B-cell) development and activation and has been a validated target for the treatment of B-cell malignancies. Herein, we report a series of thienopyrimidine derivatives as novel potent and selective PI3Kδ inhibitors based on a scaffold hopping design strategy. Among them, compound 6 exhibited nanomolar PI3Kδ potency and a favorable selectivity profile compared to other class I PI3K isoforms. In cellular assays, compound 6 showed antiproliferative activity against a panel of B-cell lymphoma cell lines in a low micromolar range, caused cell cycle arrest, and induced apoptosis in Pfeiffer and SU-DHL-6 cells. Further, compound 6 inhibited the activation of mouse B-cells. With support from in vivo pharmacokinetic studies, compound 6 demonstrated significant anticancer efficacy in a Pfeiffer xenograft mouse model. Overall, compound 6 is a promising PI3Kδ inhibitor worthy of further preclinical investigation for the treatment of B-cell malignancies.
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Antineoplásicos , Neoplasias , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Linfocitos B/metabolismo , Proliferación Celular , Fosfatidilinositol 3-Quinasa Clase I , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , PirimidinasRESUMEN
Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors. Brain metastasis, such as breast cancer and lung cancer, also leads to high mortality. The available medicines are limited due to blood-brain barrier. Abnormal activation of phosphatidylinositol 3-kinases (PI3K) signaling pathway is prevalent in glioblastoma and metastatic tumors. Here, we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3K inhibitor with excellent anti-tumor activity against human glioblastoma. XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3K signaling pathway, induced cell cycle arrest in G1 phase as well. Additionally, XH30 inhibited the migration of glioma cells and blocked the activation of PI3K pathway by interleukin-17A (IL-17A), which increased the migration of U87MG. Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models. XH30 also repressed tumor growth in brain metastasis models of lung cancers. Moreover, XH30 reduced IL-17A and its receptor IL-17RA in vivo. These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.
RESUMEN
Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)-based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog-triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.
RESUMEN
Aberrant activation of the PI3K pathway has been intensively targeted for cancer therapeutics for decades, leading to more than 40 PI3K inhibitors advanced into clinical trials. However, it is increasingly noticed that PI3K inhibitors often showed limited efficacy as well as a number of serious on-target adverse effects during the clinical development. In this work, we designed and synthesized a novel photocaged PI3K inhibitor 1, which could be readily activated by UV irradiation to release a highly potent PI3K inhibitor 2. Upon UV irradiation, the photocaged inhibitor 1 demonstrated remarkably enhanced antiproliferative activity against multiple cancer cell lines and significant efficacy in the patient-derived tumor organoid model. Furthermore, 1 also showed favorable anticancer activity in an in vivo zebrafish xenograft model. Taken together, the photocaged PI3K inhibitor 1 represents a promising avenue for novel therapeutics toward precise cancer treatment.
Asunto(s)
Diseño de Fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Animales , Sitios de Unión , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Perros , Estabilidad de Medicamentos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Transducción de Señal/efectos de los fármacos , Rayos Ultravioleta , Ensayos Antitumor por Modelo de Xenoinjerto , Pez Cebra/metabolismoRESUMEN
As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.
Asunto(s)
Antineoplásicos/química , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Pirimidinas/química , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Unión Proteica , Conformación Proteica , Pirimidinas/farmacología , Transducción de Señal , Relación Estructura-ActividadRESUMEN
A series of novel 2-pyridyl, 4-morpholinyl substituted thiazolo[5,4-b]pyridine analogues have been designed and synthesized in this paper. These thiazolo[5,4-b]pyridines were efficiently prepared in seven steps from commercially available substances in moderate to good yields. All of these N-heterocyclic compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) analysis and tested for phosphoinositide 3-kinase (PI3K) enzymatic assay. The results indicated that these N-heterocyclic compounds showed potent PI3K inhibitory activity, and the IC50 of a representative compound (19a) could reach to 3.6 nm. The structure-activity relationships (SAR) study showed that sulfonamide functionality was important for PI3Kα inhibitory activity, and 2-chloro-4-florophenyl sulfonamide (19b), or 5-chlorothiophene-2-sulfonamide (19c) showed potent inhibitory activity with a nanomolar IC50 value. The pyridyl attached to thiazolo[5,4-b]pyridine was another key structural unit for PI3Kα inhibitory potency, and replacement by phenyl lead to a significant decrease in activity. Enzymatic Inhibition results showed that compound 19a inhibited PI3Kα, PI3Kγ, or PI3Kδ with a nanomolar IC50 value, but its inhibitory activity on PI3Kß was approximately 10-fold reduced. Further docking analysis revealed that the N-heterocyclic core of compound 19a was directly involved in the binding to the kinase through the key hydrogen bonds interaction.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Piridinas/química , Piridinas/síntesis química , Animales , Activación Enzimática/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
The tubulin colchicine binding site has been recognized as an attractive drug target to combat cancer, but none of the candidate drugs have been approved for medical treatment. We recently identified a structurally distinct small molecule S-40 as an oral potent tubulin destabilizing agent. Crystal structure analysis of S-40 in a complex with tubulin at a resolution of 2.4 Å indicated that S-40 occupies all 3 zones in the colchicine pocket with interactions different from known microtubule inhibitors, presenting unique effects on assembly and curvature of tubulin dimers. S-40 overcomes paclitaxel resistance and lacks neurotoxicity, which are the main obstacles limiting clinical applications of paclitaxel. Moreover, S-40 harbors the ability to inhibit growth of cancer cell lines as well as patient-derived organoids, induce mitotic arrest and cell apoptosis. Xenograft mouse models of human prostate cancer DU145, non-small cell lung cancer NCI-H1299 and paclitaxel-resistant A549 were strongly restrained without apparent side effects by S-40 oral administration once daily. These findings provide evidence for the development of S-40 as the next generation of orally effective microtubule inhibitors for cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Moduladores de Tubulina/administración & dosificación , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Células A549 , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Colchicina/química , Colchicina/farmacología , Cristalografía por Rayos X , Humanos , Masculino , Ratones , Modelos Moleculares , Neoplasias/metabolismo , Paclitaxel/farmacología , Conformación Proteica , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The limitations of arene C-H functionalization of aryl sulfonamides containing strongly coordinating N-heterocycles were overcome using a Rh(iii) catalyst. The site-selectivity of C-H carbenoid functionalization at the ortho position relative to either the sulfonamide or N-heterocycle directing groups was elegantly switched using solvents of different polarities and different additive concentrations. Importantly, sulfonamide-group-directed ortho-C-H carbenoid functionalization tolerated strongly coordinating N-heterocycles, including pyridine, pyrrole, thiazole, pyrimidine, and pyrazine. Density functional theory (DFT) calculations were performed to rationalize the reaction mechanisms and the influence of reaction polarity.
RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease, and its molecular pathogenesis remains poorly understood. Recently, emerging evidence demonstrates that the PI3K signaling transduction pathway is linked to the pathology of IPF. In this work, we rationally designed a new series of 4-methylquinazoline derivatives as highly potent PI3K inhibitors that significantly suppress the phosphorylation of the main PI3K downstream effectors and displays marked antiproliferative activity in mouse MLg2908 lung fibroblasts. In a bleomycin-induced mouse pulmonary fibrosis model, 5d from the series improved mouse lung function and slowed the progression of pulmonary fibrosis. Overall, this work promises a therapeutic potential for PI3K inhibitors to treat IPF.
Asunto(s)
Fosfatidilinositol 3-Quinasas/química , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Quinazolinas/química , Animales , Bleomicina/toxicidad , Línea Celular , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/patología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Pulmón/metabolismo , Ratones , Ratones Endogámicos ICR , Conformación Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Fosforilación/efectos de los fármacos , Quinazolinas/metabolismo , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
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Antineoplásicos/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Inhibidores de Histona Desacetilasas/metabolismo , Histona Desacetilasas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Células HCT116 , Células Hep G2 , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Células K562 , Células MCF-7 , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular/métodos , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacologíaRESUMEN
NSCLC is a worldwide challenge due to its high incidence and poor survival. PI3K-Akt-mTOR (PAM) pathway is one of the major pathways that mediate receptor tyrosine kinases (RTKs) signalling transduction. Aberration in PAM pathway is indicated correlating with poor prognosis of NSCLC. In this article, we highlighted a 2-amino-4-methylquinazoline derivative XH002 as PI3K/mTOR dual inhibitor with outstanding antitumor efficacy. Briefly, XH002 significantly repressed proliferation of PI3KCA mutant and/or P-S6RP, P-RAS40 high expressed NSCLC cells. In vitro, XH002 decreased the phosphorylation of PAM pathway proteins in a dose-dependent and time-dependent way. Further investigation indicated that the cancer cells repression by XH002 derived from inducing cell cycle arrest in G1 phase. Moreover, XH002 remarkably inhibited tumour growth of EGFR-TKIs resistant NCI-H1975 xenograft model by blocking PAM pathway. In conclusion, XH002 is a potent oral PI3K/mTOR dual inhibitor that possesses excellent antitumor efficacy against PIK3CA mutant NSCLC, including which resistant to EGFR-TKIs treatments.