RESUMO
Glucagon-like peptide-1 receptor (GLP-1R) is a pivotal receptor involved in blood glucose regulation and influencing feeding behavior. It has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. Peptide GLP-1 receptor agonists (GLP-1RAs) have achieved tremendous success in the market, driving the vigorous development of small molecule GLP-1RAs. Currently, several small molecules have entered the clinical research stage. Additionally, recent discoveries of GLP-1R positive allosteric modulators (PAMs) are also unveiling new regulatory patterns and treatment methods. This article reviews the structure and functional mechanisms of GLP-1R, recent reports on small molecule GLP-1RAs and PAMs, as well as the optimization process. Furthermore, it combines computer simulations to analyze structure-activity relationships (SAR) studies, providing a foundation for exploring new strategies for designing small molecule GLP-1RAs.
Assuntos
Desenho de Fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1 , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Relação Estrutura-Atividade , Sítios de Ligação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Estrutura Molecular , Animais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese químicaRESUMO
NTRK gene fusion leads to the activation of downstream signaling pathways, which is a oncogenic driver in various cancers. NTRK fusion-positive cancers can be treated with the first-generation TRK inhibitors, larotrectinib and entrectinib. Unfortunately, the patients eventually face the dilemma of no drugs available as the emergence of certain resistance mutations. The development of efficient and broad-spectrum second-generation TRK inhibitors is still of great significance. Here, we analyzed the binding modes of compounds 6, 10 with TRKA protein, respectively, a series of novel indazole TRK inhibitors were designed and synthesized using molecular hybridization strategy. Among them, the optimal compound B31 showed strong antiproliferative activities against Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell lines with IC50 values of 0.3, 4.7, and 9.9 nM, respectively. And the inhibitory effect against TRKAG667C (IC50 = 9.9 nM) was better than that of selitrectinib (IC50 = 113.1 nM). Further, compound B31 exhibited moderate kinase selectivity and excellent plasma stability (t1/2 > 480 min). In vivo pharmacokinetic studies in Sprague-Dawley rats showed that B31 had acceptable pharmacokinetic properties.
Assuntos
Antineoplásicos , Proliferação de Células , Descoberta de Drogas , Indazóis , Inibidores de Proteínas Quinases , Ratos Sprague-Dawley , Receptor trkA , Indazóis/farmacologia , Indazóis/química , Indazóis/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Humanos , Animais , Relação Estrutura-Atividade , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Proliferação de Células/efeitos dos fármacos , Ratos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , MasculinoRESUMO
Droughts and heat waves exhibit synergistic effects and are among the world's most costly disasters. To explore the spatiotemporal differences and formation mechanisms of the combined vulnerability to droughts and heat waves in Shandong Province over the past 20 years, a vulnerability scoping diagram (VSD) model with three dimensions-exposure, sensitivity, and adaptability-was constructed to assess and compare the combined vulnerability to high-temperature and drought events, considering economic and social conditions. The results showed that (1) over the past 20 years, heat waves and droughts have increased in Shandong Province. The number of high-temperature events significantly increased in the west and decreased along the eastern coast, and drought change was characterized by an increase in the south and a decrease in the north. (2) The combined exposure to summer droughts and heat waves in Shandong Province showed a significant increasing trend (P < 0.05) at a rate of approximately 0.072/10a; the combined sensitivity significantly decreased (P < 0.05) at a rate of approximately 0.137/10a, and the combined adaptability continued to increase at a rate of approximately 0.481/10a. (3) The combined vulnerability to summer droughts and heat waves in the western inland area of Shandong Province was high and gradually decreased toward the southeastern coast. The overall decrease trend was nonsignificant with a decrease of approximately 0.126/10a, and the decline rate decreased from northwest to southeast, in which Laiwu, Yantai, Jinan, and Zibo cities exhibited a significant decreasing trend (P < 0.05). Although the compound vulnerability of Shandong Province has decreased insignificantly, the frequency of combined drought and heat wave events has increased, and the combined vulnerability will increase in the future.
Assuntos
Secas , Monitoramento Ambiental , Estações do Ano , China , Monitoramento Ambiental/métodos , Temperatura Alta , Mudança ClimáticaRESUMO
Tropomyosin receptor kinase (TRK) is a promising target for treating NTRK fusion cancers. The solvent front and xDFG mutations induced by larotrectinib and entrectinib result in acquired resistance in advanced-stage patients. In this study, we report a highly potent and selective type II TRK inhibitor, 40l, developed using a structure-based design strategy. Compound 40l significantly suppressed Km-12, Ba/F3-TRKAG595R, and Ba/F3-TRKAG667C cell proliferation. In biochemical and cellular assays, 40l showed better inhibitory activity against TRKAG667C than that by the positive control, selitrectinib. Additionally, it induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Furthermore, 40l showed good selectivity for a panel of 41 kinases. In vitro assays indicated that 40l possessed outstanding plasma stability and moderate liver microsomal stability. Based on the above results, compound 40l could be further optimized to overcome the solvent front and xDFG TRK mutations.
Assuntos
Neoplasias , Receptor trkA , Humanos , Neoplasias/genética , Indazóis/farmacologia , Solventes , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor protein tyrosine kinase that belongs to the family of focal adhesion complexes and is responsible for the development of various tumors. Herein, 24 diaminopyrimidine derivatives were designed and synthesized based on TAE-226. Several compounds with good activity were further evaluated regarding their antiproliferative activities against two cancer cells with high FAK expression. Compound A12 showed potent anticancer activity against A549 and MDA-MB-231 cell lines with IC50 values of 130 nM and 94 nM, respectively. In vitro metabolic stability and cytochrome P450 (CYP) inhibition assays showed that A12 exhibited favorable stability and weak inhibitory activity on CYP isoforms. Preliminary evaluation of kinase selectivity showed that A12 was a multi-kinase inhibitor. The acute toxicity in vivo indicated that A12 possessed acceptable safety. Compound A12 was also selected for molecular docking studies and the prediction of molecular properties and drug-like properties. These results indicated that compound A12 could be used as a potential lead compound targeting FAK for further development.
RESUMO
Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure-activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. SP27 exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimera de Direcionamento de Proteólise , Linhagem Celular Tumoral , Células MCF-7 , Relação Estrutura-Atividade , Proteólise , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Proteínas Serina-Treonina QuinasesRESUMO
Tropomyosin receptor kinases (TRKs) are effective targets for anti-cancer drug discovery. The first-generation type I TRKs inhibitors, larotrectinib and entrectinib, exhibit durable disease control in the clinic. The emergence of acquired resistance mediated by secondary mutations in the TRKs domain significantly reduces the therapeutic efficacy of these two drugs, indicating an unmet clinical need. In this study, we designed a potent and orally bioavailable TRK inhibitor, compound 24b, using a molecular hybridization strategy. Compound 24b exhibited significant inhibitory potency against multiple TRK mutants in both biochemical and cellular assays. Furthermore, compound 24b induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Additionally, compound 24b exhibited moderate kinase selectivity. In vitro stability revealed that compound 24b showed excellent plasma stability (t1/2 > 289.1 min) and moderate liver microsomal stability (t1/2 = 44.3 min). Pharmacokinetic studies have revealed that compound 24b is an orally bioavailable TRK inhibitor with a good oral bioavailability of 116.07%. These results indicate that compound 24b be used as a lead molecule for further modifications to overcome drug-resistant mutants of TRK.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Receptor trkA , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/químicaRESUMO
[This corrects the article DOI: 10.3389/fimmu.2022.950441.].
RESUMO
Tropomyosin receptor kinases (TRKs) are associated with the proliferation and differentiation of cells, and thus their continuous activation and overexpression cause cancer. Herein, based on scaffold hopping and computer-aid drug design, 38 pyrazolo[3,4-b]pyridine derivatives were synthesised. Further, we evaluated their activities to inhibit TRKA. Among them, compound C03 showed acceptable activity with an IC50 value of 56 nM and it inhibited the proliferation of the Km-12 cell line with an IC50 value of 0.304 µM together with obvious selectivity for the MCF-7 cell line and HUVEC cell line. Furthermore, compound C03 possessed good plasma stability and low inhibitory activity to a panel of cytochrome P450 isoforms except CYP2C9. Overall, C03 has potential for further exploration.
RESUMO
Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure-activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.
Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Camundongos , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células K562 , Inibidores de Proteínas Quinases/farmacologia , Proliferação de Células , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Tropomyosin receptor kinase (TRK) is a successful target for the treatment of various cancers caused by NTRK gene fusions. Herein, based on a rational drug design strategy, we designed and synthesized 35 aminopyrimidine derivatives that were shown to be TRKA inhibitors in the enzyme assay, among which compounds C3, C4, and C6 showed potent inhibitory activities against TRKA with IC50 values of 6.5, 5.0, and 7.0 nM, respectively. In vitro antiproliferative activity study showed that compound C3 significantly inhibited the proliferation of KM-12 cells but had weak inhibitory effect on MCF-7 cells and HUVEC cells. The preliminary druggability evaluation showed that compound C3 exhibited favorable liver microsomal and plasma stabilities and had weak or no inhibitory activity against cytochrome P450 isoforms at 10 µM. Compounds C3, C4, and C6 were also selected for ADME (absorption, distribution, metabolism, and elimination) properties prediction and molecular docking studies. Inhibition experiments showed that compound C3 was not selective for TRK subtypes. All results indicated that compound C3 was a useful candidate for the development of TRK inhibitors.
Assuntos
Antineoplásicos , Receptor trkA , Humanos , Receptor trkA/genética , Receptor trkA/metabolismo , Tropomiosina/metabolismo , Tropomiosina/farmacologia , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Aminopiridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Desenho de Fármacos , Antineoplásicos/farmacologia , Proliferação de CélulasRESUMO
Objective: The occurrence of cardiovascular adverse events in the first year after ST-acute myocardial infarction (STEMI) remains high; therefore, identification of patients with poor prognosis is essential for early intervention. This study aimed to evaluate the prognostic value of metabolomics-based biomarkers in STEMI patients and explore their functional mechanisms. Methods: Metabolite profiling was performed using nuclear magnetic resonance. The plasma concentration of Kynurenine (Kyn) was measured using ultraperformance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Major adverse cardiac and cerebral events were assessed for 1 year. A functional metabolomics strategy was proposed for investigating the role of Kyn in both vitro and vivo models. Results: The adjusted hazard ratios in STEMI patients for Kyn in the 4th quartile 7.12(5.71-10.82) was significantly higher than that in the 3rd quartile 3.03(2.62-3.74), 2nd quartile 1.86(1.70-2.03), and 1st quartile 1.20(0.93-1.39).The incidence of MACCE was significantly different among Kyn quartiles and the highest incidence of MACCE was observed in the 4th quartile when compared with the 1st quartile (9.84% vs.2.85%, P<0.001).Immunofluorescence staining indicated that indoleamine-pyrrole 2,3-dioxygenase (IDO1) was located in the CD68 positive staining area of thrombi from STEMI patients and Kyn was induced in the early phase after myocardial infarction. Kyn could trigger inflammation and oxidative stress of macrophage cells by activation of the Sirt3-acSOD2/IL-1ß signaling pathway in vitro. Conclusions: Plasma Kyn levels were positively associated with the occurrence of STEMI. Kyn could induce macrophage cells inflammation and oxidative stress by activating the Sirt3-acSOD2/IL-1ß pathway following myocardial ischemia injury. Kyn could be a robust biomarker for STEMI prognosis and reduction of Kyn could be beneficial in STEMI patients.
Assuntos
Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Sirtuína 3 , Humanos , Cinurenina , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Prognóstico , Infarto do Miocárdio/complicações , Metabolômica , Biomarcadores , Inflamação/complicaçõesRESUMO
Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase involved in regulating cell mitosis and centriole duplication, and has emerged as a therapeutic target for treating multiple cancers. At first, the design and in vitro validation of PLK4 inhibitors (12a-12e, 17a-17f, 22a-22e) bearing 1H-pyrazolo[3,4-b]pyridine scaffold was described and lead compound 22a (IC50 = 0.106 µM) was identified. Then, selectivity- and activity-guided development of a series of potent and selective type-II PLK4 inhibitors using a homology model approach was carried out. Further structure-based optimization resulted in a potent type-II PLK4 inhibitor 29u (IC50 = 0.026 µM), which exhibited outstanding selectivity in a panel of 47 kinases at a single concentration of 1.0 µM. Furthermore, compound 29u significantly inhibited the proliferation of breast cancer cell line MCF-7 with an IC50 value of 1.52 µM, while it exhibited no inhibitory effect on normal cell lines (L02 and HUVECs). Meanwhile, the clone formation, senescence and migration abilities of compound 29u were evaluated using MCF-7 cells. The detailed biological evaluation revealed that compound 29u could arrest cell division in S/G2 phase by inhibiting PLK4, and then affect the expression of downstream signalling pathway proteins regulated by PLK4. Moreover, the in vitro preliminary evaluation of the drug-like properties of compound 29u exhibited outstanding plasma stability, moderate liver microsomal stability, and low risk of drug-drug interactions (DDIs). The current discovery will support the further development of compound 29u as a lead compound for PLK4-targeted anticancer drug discovery and as a useful chemical probe for the further biological research of PLK4.
Assuntos
Antineoplásicos , Ureia , Humanos , Ureia/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Mitose , Células MCF-7 , Ciclo Celular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Proliferação de Células , Linhagem Celular Tumoral , Proteínas Serina-Treonina QuinasesRESUMO
Invasive fungal infections are emerging as serious infectious diseases worldwide. Due to the frequent emergence of resistance, the cure for invasive fungal infections is often unachievable. The molecular chaperone Hsp90 provides a promising target because it supports survival, virulence, and drug resistance in a variety of pathogens. Herein, we report on the structural optimization and structure-activity relationship studies of 3,4-isoxazolediamide analogs. As a new class of fungal Hsp90 inhibitor, compound B25 was found to have good synergistic effects with fluconazole and to avoid potential mammalian toxicity. It also showed remarkable metabolic stability in vitro. Collectively, B25 could be a promising lead compound for drug discovery targeting fungal Hsp90 and deserves further investigation.
Assuntos
Candidíase , Infecções Fúngicas Invasivas , Humanos , Antifúngicos/farmacologia , Azóis/farmacologia , Azóis/uso terapêutico , Candida albicans , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Farmacorresistência Fúngica , Proteínas de Choque Térmico HSP90 , Infecções Fúngicas Invasivas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Relação Estrutura-AtividadeRESUMO
FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T1/2 >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.
Assuntos
Antineoplásicos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Fosforilação , ProteóliseRESUMO
Lysine-specific demethylase 1 (LSD1) is a FAD-dependent histone demethylase to catalyze the demethylation of H3K4 and H3K9 and thus is an attractive target for therapeutic cancer. Starting with a high micromolar compound 17i, structure-based optimization of novel indole derivatives is described by a bioelectronic isosteric strategy. Grounded by molecular modeling, medicinal chemistry has efficiently yielded low nanomolar LSD1 inhibitors. One of the compounds, B35, exhibited excellent LSD1 inhibition (IC50 = 0.050 ± 0.005 µM) and anti-proliferation against A549 cells (IC50 = 0.74 ± 0.14 µM). The further PK studies indicated compound B35 possessed favorable metabolic stability, in which the plasma t1/2 of p.o. and i.v. were 6.27 ± 0.72 h and 8.78 ± 1.31 h, respectively. Additionally, inhibitor B35 shows a strong antitumor effect and good safety in vivo. Meanwhile, compound B35 regulated genes are closely associated with transcriptional dislocation in cancer and PI3K/AKT pathway involving IGFBP3. Taken together, B35 could be a potent LSD1 inhibitor for further drug development.
Assuntos
Inibidores Enzimáticos , Histona Desmetilases , Indóis , Células A549 , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Humanos , Indóis/síntese química , Indóis/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Herein, we report the discovery process and antitumor activity of the TRK inhibitor CZw-124 (8o), which is a quinazoline derivative. Starting from a PAK4 inhibitor, we used various drug design strategies, including pharmacophore feature supplementation, F-scanning, and blocking metabolic sites, and finally found a TRK inhibitor CZw-124 that is effective in vitro and in vivo. Docking studies and molecular dynamics simulations revealed a possible mode of binding of CZw-124 to TRKA. Biological activity evaluation showed that CZw-124 belongs to a class of pan-TRK inhibitors with moderate kinase selectivity. It inhibited the proliferation and induced the apoptosis of Km-12 cells in vitro by interfering with the phosphorylation of TRKA. Pharmacodynamic evaluation in vivo showed that CZw-124 had a tumor inhibition rate comparable to that of larotrectinib after oral administration of 40 mg/kg/d (tumor growth inhibiton = 71%).
Assuntos
Neoplasias , Receptor trkA , Desenho de Fármacos , Humanos , Neoplasias/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Quinases Ativadas por p21RESUMO
Serine/threonine-protein kinase polo-like kinase 4 (PLK4) is a mitosis-associated protein kinase that plays a vital role in the duplication of centrioles in dividing cells and is considered a promising target of synthetic lethality in TRIM37-amplified breast cancer. Herein, based on a rational drug design strategy, we described a series of pyrazolo [3,4-d]pyrimidine derivatives as potent PLK4 inhibitors and dissected the relevant structure-activity relationships (SARs). Most compounds showed potent suppressive activities against PLK4, with IC50 values of < 10 nM. Among them, compound 24j (PLK4 IC50 = 0.2 nM) displayed potent enzyme inhibition and good selectivity in a panel of 35 kinases. At the cellular level, compound 24j exhibited notable antiproliferative activities against MCF-7, BT474, and MDA-MB-231 cells, with IC50 values of 0.36, 1.35, and 2.88 µM, respectively. Compound 24j killed TRIM37-amplified breast cancer cells. Moreover, we evaluated the clone formation, proliferation, cycle arrest, and migration abilities of compound 24j using MCF-7 cells. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 24j showed remarkable plasma stability, moderate liver microsomal stability, and weak inhibitory activity against the main subtypes of human cytochrome P450. Based on in vivo pharmacokinetic studies in Sprague Dawley rats, compound 24j exhibited a relatively high plasma clearance and a low F value (8.03%). Overall, these results support the further development of compound 24j as a potential lead compound to treat TRIM37-amplified breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Animais , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The intracellular non-receptor tyrosine protein kinase Focal adhesion kinase (FAK) is a key signalling regulator, which mediates tumor survival, invasion, metastasis, and angiogenesis through its kinase catalytic functions and non-kinase scaffolding functions. Previous efforts have clarified that it is crucial to address both FAK kinase and scaffolding functions instead of just inhibiting FAK kinase activity because it may be insufficient to completely block FAK signaling. Proteolysis targeting chimera (PROTAC) technology is a method of targeting a specific protein and inducing its degradation in the cell, which can simultaneously eliminate both kinase-dependent enzymatic functions and scaffolding functions. In current study, we designed and synthesized a series of novel FAK PROTACs and the optimal PROTAC B5 exhibited potent FAK affinity with an IC50 value of 14.9 nM. Furthermore, in A549 cells, PROTAC B5 presented strong FAK degradation activity (86.4% degradation @ 10 nM), powerful antiproliferative activity (IC50 = 0.14 ± 0.01 µM) and inhibited cell migration and invasion in a concentration-dependent manner. Additionally, the in vitro preliminary drug-like properties evaluation of PROTAC B5 showed outstanding plasma stability and moderate membrane permeability. Together, current results provided a promising FAK PROTAC B5 as lead compound for cancer-related drug discovery and FAK-degradation functions exploration in biological systems.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proteína-Tirosina Quinases de Adesão Focal , Neoplasias Pulmonares , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desenho de Fármacos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , ProteóliseRESUMO
Invasive fungal infections are emerging as serious infectious diseases worldwide. Because of the development of antifungal drug resistance, the limited efficacy of the existing drugs has led to high mortality in patients. The use of the essential eukaryotic chaperone Hsp90, which plays a multifaceted role in drug resistance across diverse pathogenic fungal species, is considered to be a new strategy to mitigate the resistance and counter the threat posed by drug-resistant fungi. Thus, a series of 4,5-diarylisoxazole analogues as fungal Hsp90 inhibitors were designed and synthesized that had potent synergistic effects with fluconazole in vitro and in vivo. In particular, compound A17 could avoid the potential mammalian toxicity of Hsp90 inhibitors based on key reside differences between humans and fungi. These data support the feasibility of targeting fungal Hsp90 as a promising antifungal strategy and further development of compound A17 as a valuable research probe for the investigation of fungal Hsp90.