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1.
Eur J Med Chem ; 271: 116435, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38648728

RESUMO

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo , Bibliotecas de Moléculas Pequenas , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/química , Inibidores de Proteassoma/uso terapêutico , Estrutura Molecular
3.
J Med Chem ; 67(6): 4346-4375, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38484122

RESUMO

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.


Assuntos
Neoplasias Pulmonares , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas c-ret/genética , Medicina de Precisão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Neoplasias Pulmonares/tratamento farmacológico
4.
J Med Chem ; 67(5): 4194-4224, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38442261

RESUMO

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.


Assuntos
Corantes Fluorescentes , Células Th17 , Corantes Fluorescentes/farmacologia , Fatores de Transcrição , Regulação da Expressão Gênica , Polarização de Fluorescência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo
5.
Bioorg Med Chem ; 100: 117631, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38330848

RESUMO

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Humanos , Apoptose , Linhagem Celular Tumoral , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Piridinas/farmacologia
6.
Biomed Pharmacother ; 169: 115905, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38000356

RESUMO

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Animais , Camundongos , Peixe-Zebra , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mutação
7.
Eur J Med Chem ; 260: 115726, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37597436

RESUMO

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.


Assuntos
Produtos Biológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Antivirais/farmacologia , Produtos Biológicos/farmacologia , Movimento Celular
8.
Eur J Med Chem ; 257: 115464, 2023 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-37235998

RESUMO

Glioma is one of the most common types of brain tumors, and its high recurrence and mortality rates threaten human health. In 2008, the frequent isocitrate dehydrogenase 1 (IDH1) mutations in glioma were reported, which brought a new strategy in the treatment of this challenging disease. In this perspective, we first discuss the possible gliomagenesis after IDH1 mutations (mIDH1). Subsequently, we systematically investigate the reported mIDH1 inhibitors and present a comparative analysis of the ligand-binding pocket in mIDH1. Additionally, we also discuss the binding features and physicochemical properties of different mIDH1 inhibitors to facilitate the future development of mIDH1 inhibitors. Finally, we discuss the possible selectivity features of mIDH1 inhibitors against WT-IDH1 and IDH2 by combining protein-based and ligand-based information. We hope that this perspective can inspire the development of mIDH1 inhibitors and bring potent mIDH1 inhibitors for the treatment of glioma.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Isocitratos , Ligantes , Isocitrato Desidrogenase/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Mutação
9.
ACS Med Chem Lett ; 14(4): 411-416, 2023 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-37077394

RESUMO

The orphan G protein-coupled receptor 35 (GPR35) is a potential target for the treatment of pain, inflammation, and metabolic diseases. Although many GPR35 agonists have been discovered, research on functional GPR35 ligands, such as fluorescent probes, is still limited. Herein, we developed a series of GPR35 fluorescent probes by conjugating a BODIPY fluorophore to DQDA, a known GPR35 agonist. All probes exhibited excellent GPR35 agonistic activity and desired spectroscopic properties, as determined by the DMR assay, bioluminescence resonance energy transfer (BRET)-based saturation, and kinetic binding experiments. Notably, compound 15 showed the highest binding potency and the weakest nonspecific BRET binding signal (K d = 3.9 nM). A BRET-based competition binding assay with 15 was also established and used to determine the binding constants and kinetics of unlabeled GPR35 ligands.

10.
Drug Dev Res ; 84(2): 296-311, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36644989

RESUMO

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Aminas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/farmacologia , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Apoptose , Proliferação de Células
11.
Future Med Chem ; 15(1): 57-71, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36651264

RESUMO

Aim: The clinical benefits of FLT3 inhibitors against acute myeloid leukemia (AML) have been limited by selectivity and resistance mutations. Thus, to identify FLT3 inhibitors possessing high selectivity and potency is of necessity. Methods & results: The authors used computational methods to systematically compare pocket similarity with 269 kinases. Subsequently, based on these investigations and beginning with in-house compound 10, they synthesized a series of 6-methyl-isoxazol[3,4-b]pyridine-3-amino derivatives and identified that compound 45 (IC50: 103 nM) displayed gratifying potency in human AML cell lines with FLT3-internal tandem duplications mutation as well as FLT3-internal tandem duplications-tyrosine kinase domain-transformed BaF3 cells. Conclusion: The integrated biological activity results indicated that compound 45 deserves further development for therapeutic remedies for AML.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases , Mutação , Linhagem Celular , Apoptose , Tirosina Quinase 3 Semelhante a fms/genética , Linhagem Celular Tumoral
12.
Bioorg Chem ; 131: 106308, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36516520

RESUMO

Muscarine acetylcholine receptors (mAChRs) regulate a variety of central and peripheral physiological functions and emerge as important therapeutic targets for a number of diseases including chronic obstructive pulmonary disease (COPD). Inspired by two active natural products, we designed and synthesized a series of 2-(2,2-diarylethyl)-cyclamine derivatives for screening M3 mAChR antagonists. On this skeleton, the structural units including N heterocycle, aryl groups and its substituents on aryl were examined and resulted in a clear structure-activity relationships on the M3 mAChR. In general, these 2-(2,2-diarylethyl)-cyclamine derivatives exhibited good to excellent M3 antagonistic potency and receptor selectivity. The most active 5b-C1 had an IC50 value of 3 nM and the most of compound 6 displayed inactivity against histamine H1 receptor closely related to M3. In in vitro and in vivo evaluations of tracheo-relaxation function, some compounds even showed comparable activity to tiotropium bromide, a known blockbuster drug for COPD. Such excellent properties made these novel compounds potential candidates for COPD drug development.


Assuntos
Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Humanos , Antagonistas Muscarínicos/uso terapêutico , Derivados da Escopolamina/química , Derivados da Escopolamina/uso terapêutico , Receptor Muscarínico M3 , Brometo de Tiotrópio/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
13.
Chem Biol Interact ; 367: 110199, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36174740

RESUMO

ATP citrate lyase (ACLY) is a key enzyme in glucolipid metabolism with therapeutic prospect for treating hyperlipidemia and various cancers. Much effort has been put into discovering ACLY inhibitors. However, current screening approaches have limitations in sensitivity, portability and high-throughput. To develop a general screening assay, we investigated series of conditions affecting the enzymatic reaction based on the ADP-Glo luminescence assay. Bovine serum albumin (0.001%) added triggered strong and stable fluorescence signal. The optimized assay was validated and applied to screen our natural product library. Two novel inhibitors were identified with IC50 values of 3.86 ± 0.62 µM (2) and 15.48 ± 2.51 µM (4). Their aggregations and target specificities were also examined. 2 was characterized as a noncompetitive inhibitor of ACLY, while 4 was a competitive inhibitor of CoA, which was also elucidated by docking studies. In anticancer activity evaluation, 2 with higher inhibition potency did not exhibit anticancer effect, probably owing to its insufficient cell-permeability. 4 showed moderate inhibition in the proliferation of A549 and PC3 cells. This study not only developed a general approach for ACLY inhibitor discovery, but also identified a new scaffold ACLY inhibitor, which could be served as a hit compound in drug design.


Assuntos
ATP Citrato (pro-S)-Liase , Produtos Biológicos , ATP Citrato (pro-S)-Liase/metabolismo , Difosfato de Adenosina , Produtos Biológicos/farmacologia , Coenzima A/metabolismo , Luminescência , Soroalbumina Bovina
14.
Bioorg Med Chem ; 70: 116937, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35863236

RESUMO

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Aminas/farmacologia , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Mutação , Inibidores de Proteínas Quinases/química , Tirosina Quinase 3 Semelhante a fms
15.
J Med Chem ; 64(23): 17384-17402, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34709043

RESUMO

Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.


Assuntos
Anemia/tratamento farmacológico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Descoberta de Drogas , Inibidores de Prolil-Hidrolase/química , Inibidores de Prolil-Hidrolase/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Camundongos , Inibidores de Prolil-Hidrolase/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Peixe-Zebra
16.
Eur J Med Chem ; 211: 112999, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33189439

RESUMO

Hypoxia-inducible factor-2 (HIF-2), a heterodimeric transcriptional protein consisting of HIF-2α and aryl hydrocarbon receptor nuclear translocator (ARNT) subunits, has a broad transcriptional profile that plays a vital role in human oxygen metabolism. M1001, a HIF-2 agonist identified by high-throughput screening (HTS), is capable of altering the conformation of Tyr281 of the HIF-2α PAS-B domain and enhancing the affinity of HIF-2α and ARNT for transcriptional activation. M1002, an analog of M1001, shows improved efficacy than M1001. However, the cocrystal structure of M1001 and HIF-2 has some defects in revealing the agonist binding mode due to the relatively low resolution, while the binding mode of M1002 remained unexplored. To in-depth understand agonist binding profiles, herein, the molecular dynamic (MD) simulations was applied to construct a stable agonist-protein model, and a possible binding mode was proposed through the analysis of the binding free energy and hydrogen bonding of the simulation results. Nine compounds were then synthesized and evaluated to verify the proposed binding mode. Among them, compound 10 manifested improved agonistic activity and reduced toxicity compared to M1002. This study provides deep insight into the binding mode of such HIF-2 agonists, which would be useful for designing novel agonists for HIF-2.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Simulação de Dinâmica Molecular , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
17.
Drug Discov Today ; 25(7): 1262-1269, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32380083

RESUMO

Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug.


Assuntos
Anemia/tratamento farmacológico , Glicina/análogos & derivados , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/uso terapêutico , Anemia/metabolismo , Animais , Descoberta de Drogas/métodos , Eritropoetina/metabolismo , Glicina/farmacologia , Glicina/uso terapêutico , Humanos
19.
Eur J Med Chem ; 188: 112033, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923857

RESUMO

A serial of naphthalenebenzimidizole-Pt complexes 1-6 were designed and synthesized as antitumor agents. In vitro antitumor assay results showed that complexes 1-6 exhibited moderate to high antiproliferative activity against Hela, HepG2, SKOV-3, NCI-H460, BEL-7404 and A549 cancer cell lines, while they displayed obvious sensitivity and selectivity against SMMC-7721 and U251 cell lines and low toxicity against normal HL-7702 cells, in comparison with cisplatin. In vivo antitumor assay results indicated that complex 1 and 5 exhibited important in vivo antiproliferative activity in the NCI-460 and SMMC-7721 models, in comparison with cisplatin, respectively. Complexes 1 and 5 exhibited better antiproliferative activity against A549CDDP and SKOV3CDDP cell lines than cisplatin, with IC50 values of 6.98 ± 0.47 µM, 5.62 ± 0.88 µM and 13.13 ± 2.11 µM, 5.30 ± 0.33 µM, respectively, while they displayed potential antiproliferation against A549 and SKOV3 cell lines, with IC50 values of 7.32 ± 0.51 µM, 5.19 ± 0.49 µM and 14.92 ± 0.11 µM, 12.19 ± 0.92 µM, indicating the introduction of naphthalenebenzimidizole into platinum-metal system may overcome the resistance. Mechanistic studies showed that the representative complexes 1 and 5 exerted the antitumor effect mainly by the obvious covalent binding with DNA and the upregulation of the expression level of intracellular topo I, showing different action mechanism from cisplatin.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Naftalenos/farmacologia , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Camundongos Nus , Estrutura Molecular , Naftalenos/química , Neoplasias Experimentais , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-Atividade
20.
Drug Discov Today ; 24(12): 2332-2340, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31541711

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2α (HIF-2α) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2α inhibitors to the promising potency of the HIF-2α inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2α has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2α in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2α allosteric inhibitors.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Regulação Alostérica/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Mutação
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