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1.
Eur J Med Chem ; 229: 114043, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34929581

RESUMO

Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.


Assuntos
Amidas/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Amidas/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Tiofenos/química , Transplante Heterólogo
2.
J Med Chem ; 64(15): 11288-11301, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34337952

RESUMO

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of 15, which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.


Assuntos
Aminoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/antagonistas & inibidores , Enzimas Multifuncionais/antagonistas & inibidores , Xantina/farmacologia , Sítio Alostérico/efeitos dos fármacos , Aminoidrolases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Modelos Moleculares , Estrutura Molecular , Enzimas Multifuncionais/metabolismo , Relação Estrutura-Atividade , Xantina/síntese química , Xantina/química
4.
J Med Chem ; 63(4): 1642-1659, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31961685

RESUMO

Indoleamine 2,3-dioxygenase (IDO1) inhibitors are speculated to be useful in cancer immunotherapy, but a phase III clinical trial of the most advanced IDO1 inhibitor, epacadostat, did not meet its primary end point and was abandoned. In previous work, we identified the novel IDO1 inhibitor N-(4-chlorophenyl)-2-((5-phenylthiazolo[2,3-c][1,2,4]triazol-3-yl)thio)acetamide 1 through high-throughput screening (HTS). Herein, we report a structure-activity relationship (SAR) study of this compound, which resulted in the potent IDO1 inhibitor 1-(4-cyanophenyl)-3-(3-(cyclopropylethynyl)imidazo[2,1-b]thiazol-5-yl)thiourea 47 (hIDO IC50 = 16.4 nM). X-ray cocrystal structural analysis revealed that the basis for this high potency is a unique sulfur-aromatic interaction network formed by the thiourea moiety of 47 with F163 and F226. This finding is expected to inspire new approaches toward the discovery of potent IDO1 inhibitors in the future.


Assuntos
Inibidores Enzimáticos/química , Imidazóis/química , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Tiazóis/química , Sítios de Ligação , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/química , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismo
5.
J Med Chem ; 62(24): 11135-11150, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31721578

RESUMO

Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.


Assuntos
Antineoplásicos/farmacologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirimidinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/química , Apoptose , Proliferação de Células , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Fosforilação , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/química , Ratos Sprague-Dawley , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms/genética
6.
J Med Chem ; 62(22): 10108-10123, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560541

RESUMO

Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Éxons , Humanos , Masculino , Camundongos Endogâmicos ICR , Camundongos Nus , Mutação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/química , Ratos , Receptor ErbB-2 , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Chem ; 62(8): 3940-3957, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-30968693

RESUMO

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.


Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/química , Mesilato de Imatinib/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/metabolismo , Ureia/farmacologia , Ureia/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
8.
J Med Chem ; 59(8): 3906-19, 2016 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-27031565

RESUMO

Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Quinase do Linfoma Anaplásico , Cristalografia por Raios X , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/química , Relação Estrutura-Atividade
9.
J Med Chem ; 59(1): 282-93, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26642377

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure-activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Relação Estrutura-Atividade
10.
J Med Chem ; 59(1): 419-30, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26653033

RESUMO

Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N'-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Inibidores Enzimáticos/farmacocinética , Humanos , Cinurenina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triptofano/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Med Chem ; 58(19): 7807-19, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26348881

RESUMO

A structure-based virtual screening strategy, comprising homology modeling, ligand-support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Relação Estrutura-Atividade , Triptofano Oxigenase/antagonistas & inibidores , Sítios de Ligação , Bases de Dados de Compostos Químicos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Triazóis/química , Triptofano Oxigenase/química , Triptofano Oxigenase/metabolismo
12.
Proc Natl Acad Sci U S A ; 110(19): E1779-87, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23610398

RESUMO

The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Centrossomo/ultraestrutura , Inibidores Enzimáticos/farmacologia , Cinetocoros/ultraestrutura , Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinase A , Aurora Quinases , Carcinoma Hepatocelular/metabolismo , Ciclo Celular , Cristalografia por Raios X , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Nus , Mitose , Transplante de Neoplasias , Fosforilação , Estrutura Terciária de Proteína
13.
J Med Chem ; 56(10): 3889-903, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23611691

RESUMO

The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.


Assuntos
Receptores ErbB/antagonistas & inibidores , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Receptores ErbB/genética , Humanos , Modelos Moleculares , Mutação , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Reação em Cadeia da Polimerase em Tempo Real , Relação Estrutura-Atividade
14.
J Med Chem ; 53(24): 8770-4, 2010 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-21090651

RESUMO

A ligand-based virtual screening strategy (a combination of pharmacophore model generation, shape-based scoring, and structure clustering analysis) was developed to discover novel SGLT2 inhibitors. The best pharmacophore model, generated from eight glycoside inhibitors, was utilized to virtually screen three chemical databases that led to the identification of three non-glycoside SGLT2 inhibitors. This is the first report of the generation of a pharmacophore model from glycosides that has then been used to discover novel non-glycosides hits.


Assuntos
Ligantes , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Células CHO , Análise por Conglomerados , Simulação por Computador , Cricetinae , Cricetulus , Bases de Dados Factuais , Desenho de Fármacos , Glicosídeos/química , Transportador 2 de Glucose-Sódio/química
15.
ChemMedChem ; 5(10): 1707-16, 2010 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-20734309

RESUMO

The need to develop safer and more effective antidiabetic drugs is essential owing to the growth worldwide of the diabetic population. Targeting the PPAR receptor is one strategy for the treatment of diabetes; the PPAR agonists rosiglitazone and pioglitazone are already on the market. Here we report the identification of a potent PPAR agonist, 15, whose PPARγ activation was more than 20 times better than that of rosiglitazone. Compound 15 was designed to incorporate an indole head with a carboxylic acid group, and 4-phenylbenzophenone tail to achieve a PPARγ EC(50) of 10 nM. Compound 15 showed the most potent PPARγ agonist activity among the compounds we investigated. To gain molecular insight into the improved potency of 15, a structural biology study and binding energy calculations were carried out. Superimposition of the X-ray structures of 15 and agonist 10 revealed that, even though they have the same indole head part, they adopt different conformations. The head part of 15 showed stronger interactions toward PPARγ; this could be due to the presence of the novel tail part 4-phenylbenzophenone, which could enhance the binding efficiency of 15 to PPARγ.


Assuntos
Benzofenonas/química , Ácidos Indolacéticos/química , PPAR gama/agonistas , Benzofenonas/síntese química , Benzofenonas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Ligação de Hidrogênio , Ácidos Indolacéticos/síntese química , Ácidos Indolacéticos/farmacologia , Indóis/química , PPAR gama/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Termodinâmica , Tiazolidinedionas/química
16.
J Med Chem ; 53(13): 4980-8, 2010 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-20550212

RESUMO

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Receptores ErbB/antagonistas & inibidores , Furanos/química , Neoplasias Pulmonares/enzimologia , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Receptores ErbB/metabolismo , Furanos/síntese química , Furanos/farmacologia , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Espectrometria de Massas de Bombardeamento Rápido de Átomos
17.
J Med Chem ; 52(8): 2618-22, 2009 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-19301897

RESUMO

Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.


Assuntos
Hidroxibutiratos/síntese química , Hipoglicemiantes/síntese química , PPAR gama/agonistas , Quinolinas/síntese química , Cristalografia por Raios X , Hidroxibutiratos/química , Hipoglicemiantes/química , Modelos Moleculares , PPAR alfa/agonistas , Isoformas de Proteínas/agonistas , Quinolinas/química , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/química
18.
J Med Chem ; 49(21): 6421-4, 2006 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-17034149

RESUMO

Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds. The results would be helpful in designing novel PPAR agonists.


Assuntos
Indóis/química , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/química , Acetatos/química , Alquilação , Sítios de Ligação , Cristalografia por Raios X , Humanos , Técnicas In Vitro , Indóis/síntese química , Indóis/farmacologia , Ligantes , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Naftalenos/química , Naftalenos/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Propionatos/química , Relação Estrutura-Atividade , Termodinâmica , Ativação Transcricional/efeitos dos fármacos
19.
J Med Chem ; 49(17): 5154-61, 2006 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-16913704

RESUMO

Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 microM, with the most potent one showing 0.3 microM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M(pro) were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M(pro) complex structures. They inhibit SARS-CoV M(pro) activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.


Assuntos
Simulação por Computador , Desenho de Fármacos , Imidazóis/farmacologia , Oxidiazóis/farmacologia , Inibidores de Proteases/farmacologia , Piridinas/farmacologia , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/enzimologia , Sulfonas/farmacologia , Proteínas Virais/antagonistas & inibidores , Sítios de Ligação , Proteases 3C de Coronavírus , Cristalografia por Raios X , Cisteína Endopeptidases/isolamento & purificação , Bases de Dados Factuais , Ligação de Hidrogênio/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Conformação Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Proteínas Virais/isolamento & purificação
20.
J Med Chem ; 49(9): 2703-12, 2006 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-16640330

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.


Assuntos
Desenho de Fármacos , PPAR gama/agonistas , PPAR gama/metabolismo , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Cristalografia por Raios X , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , PPAR gama/química , PPAR gama/genética , Estrutura Terciária de Proteína , Transcrição Gênica/genética
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