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1.
Eur J Med Chem ; 258: 115616, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37413880

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator to control downstream NF-κB and MAPK signals in the innate immune response and has been proposed as a therapeutic target for the treatment of inflammatory and autoimmune diseases. Herein, a series of IRAK4 inhibitors based on a dihydrofuro[2,3-b]pyridine scaffold was developed. Structural modifications of the screening hit 16 (IC50 = 243 nM) led to IRAK4 inhibitors with improved potency but high clearance (Cl) and poor oral bioavailability, as exemplified by compound 21 (IC50 = 6.2 nM, Cl = 43 ml/min/kg, F = 1.6%, LLE = 5.4). Structure modification aimed at improving LLE and reducing clearance identified compound 38. Compound 38 showed significantly improved clearance while maintained excellent biochemical potency against IRAK4 (IC50 = 7.3 nM, Cl = 12 ml/min/kg, F = 21%, LLE = 6.0). Importantly, compound 38 had favorable in vitro safety and ADME profiles. Furthermore, compound 38 reduced the in vitro production of pro-inflammatory cytokines in both mouse iBMDMs and human PBMCs and was orally efficacious in the inhibition of serum TNF-α secretion in LPS-induced mouse model. These findings suggested that compound 38 has development potential as an IRAK4 inhibitor for the treatment of inflammatory and autoimmune disorders.


Assuntos
Quinases Associadas a Receptores de Interleucina-1 , Transdução de Sinais , Humanos , Animais , Camundongos , NF-kappa B/metabolismo , Citocinas , Piridinas/farmacologia
2.
Bioorg Chem ; 137: 106584, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37163814

RESUMO

Interleukin-1 receptor associated kinase-4 (IRAK4) has emerged as a therapeutic target for inflammatory and autoimmune diseases. Through reversing the amide of CA-4948 and computer aided structure-activity relationship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Compound 32 showed improved potency (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 µM). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 µM) and 13-fold higher activity (IC50 = 8.9 nM) than CA-4948. Importantly, compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties. Furthermore, compound 42 significantly reduced LPS-induced production of serum TNF-α and IL-6 cytokines in the mouse model. The overall profiles of compound 42 support it as a lead for the development of IRAK4 inhibitors for the treatment of inflammatory and autoimmune disorders.


Assuntos
Citocinas , Quinases Associadas a Receptores de Interleucina-1 , Animais , Camundongos , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipopolissacarídeos/farmacologia , Síndrome de Resposta Inflamatória Sistêmica , Relação Estrutura-Atividade
3.
Blood ; 141(9): 1070-1086, 2023 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-36356302

RESUMO

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.


Assuntos
Doença Enxerto-Hospedeiro , Intestinos , Camundongos , Humanos , Animais , Mucosa Intestinal/metabolismo , Inflamação/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/metabolismo , Homeostase , Proteína Serina-Treonina Quinases de Interação com Receptores
4.
Bioorg Chem ; 129: 106051, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36115309

RESUMO

Receptor-interacting protein kinase-1 (RIPK1) is involved in the necroptosis pathway, which regulates inflammatory signaling and cell death in a variety of diseases, including inflammatory and neurodegenerative disorders. We identified a novel hit compound 36 by a cell-based screening assay (anti-necroptosis EC50 = 58 nM). Starting from compound 36, we designed a series of scaffolds to improve anti-necroptosis activity, physicochemical properties and metabolic stability. The isothiazolo[5,4-b]pyridine backbone proved to be a promising scaffold which provided a number of potent necroptosis inhibitors. Compound 56, for example, effectively blocked necroptosis in both human and mouse cells (EC50 = 1-5 nM). A binding assay showed that compound 56 potently binds to RIPK1 (Kd = 13 nM), but not RIPK3 (Kd > 10,000 nM). Kinase functional assay (ADP-Glo) confirmed that compound 56 inhibits RIPK1 phosphorylation with an IC50 at 5.8 nM. Importantly, compound 56 displayed excellent cross-species liver microsomal metabolic stability (t1/2 > 90 min). Furthermore, compound 56 exhibited favorable in vitro safety profiles in hERG and CYP assays. Finally, pre-treatment with 56 significantly reduced hypothermia and lethal shock in the systemic inflammatory response syndrome mice model. Taken together, compound 56 represented a promising prototype for the development of therapeutic agent to treat inflammation-related diseases.


Assuntos
Necroptose , Piridinas , Humanos , Camundongos , Animais , Fosforilação , Morte Celular , Piridinas/farmacologia , Síndrome de Resposta Inflamatória Sistêmica , Apoptose , Proteína Serina-Treonina Quinases de Interação com Receptores/farmacologia
5.
Future Med Chem ; 14(6): 421-442, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35167311

RESUMO

Background: Necroptosis is an important form of regulated cell death involved in inflammatory diseases, degenerative diseases and cancer. RIPK3 is an interesting target for intervention of necroptosis-associated diseases. Methodology: Herein the authors report the synthesis of a series RIPK3 inhibitors under the guidance of structure-based drug design which leads to the identification of compound 37. Results: Compound 37 potently rescued human and mouse cells from necroptotic stimuli TNF-α, Smac mimetic, z-VAD and LPS + z-VAD, displayed high affinity to RIPK3 (Kd = 14 nM) but no observable affinity to RIPK1 and inhibited RIPK3 kinase function. Importantly, compound 37 significantly alleviated TNF-induced systemic inflammatory response syndrome in the mouse model. Conclusion: These results support compound 37 as a prototype RIPK3 inhibitor for lead optimization.


Assuntos
Desenho de Fármacos , Necroptose , Animais , Modelos Animais de Doenças , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores , Fator de Necrose Tumoral alfa
6.
Eur J Med Chem ; 228: 114036, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34906762

RESUMO

RIPK1 plays a key role in the necroptosis pathway that regulates inflammatory signaling and cell death in various diseases, including inflammatory and neurodegenerative diseases. Herein, we report a series of potent RIPK1 inhibitors, represented by compound 70. Compound 70 efficiently blocks necroptosis induced by TNFα in both human and mouse cells (EC50 = 17-30 nM). Biophysical assay demonstrates that compound 70 potently binds to RIPK1 (Kd = 9.2 nM), but not RIPK3 (Kd > 10,000 nM). Importantly, compound 70 exhibits greatly improved metabolic stability in human and rat liver microsomes compared to compound 6 (PK68), a RIPK1 inhibitor reported in our previous work. In addition, compound 70 displays high permeability in Caco-2 cells and excellent in vitro safety profiles in hERG and CYP assays. Moreover, pre-treatment of 70 significantly ameliorates hypothermia and lethal shock in SIRS mice model. Lastly, compound 70 possesses favorable pharmacokinetic parameters with moderate clearance and good oral bioavailability in SD rat. Taken together, our work supports 70 as a potent RIPK1 inhibitor and highlights its potential as a prototypical lead for further development in necroptosis-associated inflammatory disorders.


Assuntos
Acetamidas/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Tiazóis/farmacologia , Acetamidas/síntese química , Acetamidas/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Células Cultivadas , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
7.
Eur J Med Chem ; 217: 113327, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33730678

RESUMO

Necroptosis is a form of regulated necrotic cell death that is independent of caspases. Receptor-interacting protein kinase 3 (RIPK3) has been identified as a key regulator for necroptosis, and has been proposed as a potential therapeutic target for the treatment of diseases associated with necroptosis. In this report, we describe the design, synthesis, and evaluation of a series of novel RIPK3 inhibitors. The lead compound 38 exhibited potent activity (EC50 = 0.42 µM) in blocking TNFα, Smac mimetic and z-VAD (TSZ) induced cell death in HT-29 cells. Mechanistic studies showed that compound 38 bound to RIPK3 with high affinity (Kd = 7.1 nM), and inhibited RIPK3 kinase activity in a ADP-Glo functional assay. In addition, compound 38 displayed good selectivity over another necroptosis regulator RIPK1 (Kd = 6000 nM). Furthermore, compound 38 demonstrated excellent in vitro safety profiles with minimal inhibition of CYP isozymes and hERG potassium channel. Lastly, compound 38 efficiently blocked hypothermia and death in mice in the TNFα-induced systemic inflammatory response syndrome model.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hipotermia/tratamento farmacológico , Hipotermia/metabolismo , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Relação Estrutura-Atividade , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/farmacologia
8.
Front Cell Dev Biol ; 8: 606119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33364238

RESUMO

Necroptosis is a form of regulated necrosis that requires the activation of receptor-interacting kinase 3 (RIPK3 or RIP3) and its phosphorylation of the substrate MLKL (mixed lineage kinase domain-like protein). Necroptosis has emerged as important cell death involved in the pathogenesis of various diseases including inflammatory diseases, degenerative diseases, and cancer. Here, we discovered a small molecule Zharp-99 as a potent inhibitor of necroptosis through blocking the kinase activity of RIPK3. Zharp-99 efficiently blocks necroptosis induced by ligands of the death receptor and Toll-like receptor as well as viral infection in human, rat and mouse cells. Zharp-99 strongly inhibits cellular activation of RIPK3, and MLKL upon necroptosis stimuli. Zharp-99 directly blocks the kinase activity of RIPK3 without affecting RIPK1 kinase activity at the tested concentration. Importantly, Zharp-99 exerts effective protection against TNF-α induced systemic inflammatory response syndrome in the mouse model. Zharp-99 displays favorable in vitro safety profiles and in vivo pharmacokinetic parameters. Thus, our study demonstrates Zharp-99 as a potent inhibitor of RIPK3 kinase and also highlights its potential for further development of new approaches for treating necroptosis-associated inflammatory disorders.

9.
Eur J Med Chem ; 205: 112537, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768738

RESUMO

The chemokine receptor CXCR4 has been proposed as a drug target based on its important functions in HIV infection, inflammation/autoimmune diseases and cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC50 = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC50 = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD7.4 1.12, pKa 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC50 > 30 µM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a cancer metastasis model in mice. These results strongly support 46 as a prototypical lead for the development of promising CXCR4 antagonists as clinical candidates.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Animais , Antineoplásicos/química , Cálcio/metabolismo , Linhagem Celular Tumoral , Técnicas de Química Sintética , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Camundongos , Metástase Neoplásica , Pirrolidinas/química , Ratos
10.
ChemMedChem ; 15(13): 1150-1162, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32391652

RESUMO

Chemokine receptor CXCR4 and its natural ligand CXCL12 (also known as stromal cell-derived factor-1, or SDF-1) regulate a broad range of physiological functions. Dysregulation of the CXCL12/CXCR4 axis is involved in numerous pathological conditions such as HIV infection, inflammation and cancer. Herein, we report the design, synthesis, and characterization of novel CXCR4 antagonists based on cyclic amine scaffolds. Compound 24 was identified as a potent CXCR4 receptor antagonist (competitive inhibition of 12G5 binding, IC50 =24 nM; functional inhibition of CXCL12-induced cytosolic calcium increase, IC50 =0.1 nM). In addition, compound 24 potently inhibited cell migration in CXCR4/CXCL12-mediated chemotaxis in a matrigel invasion assay. The absolute configuration of compound 24 was elucidated by X-ray crystallography.


Assuntos
Aminas/farmacologia , Desenho de Fármacos , Receptores CXCR4/antagonistas & inibidores , Aminas/síntese química , Aminas/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade
11.
Bioorg Chem ; 99: 103824, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32334192

RESUMO

The chemokine receptor CXCR4 has been explored as a drug target due to its involvement in pathological conditions such as HIV infection and cancer metastasis. Here we report the structure-activity relationship study of novel CXCR4 antagonists based on an aminoquinoline template. This template is devoid of the chiral center in the classical tetrahydroquinoline (THQ) ring moiety and therefore can be easily synthesized. A number of potent CXCR4 antagonists were identified, exemplified by compound 3, which demonstrated excellent binding affinity with CXCR4 receptor (IC50 = 57 nM) and inhibited CXCL12 induced cytosolic calcium increase (IC50 = 0.24 nM). Furthermore, compound 3 potently inhibited CXLC12/CXCR4 mediated cell migration in a transwell invasion assay. The simplified synthetic approach combined with good physicochemical properties (e.g. MW 362, clogP 2.1, PSA 48, pKa 7.0 for compound 3) demonstrate the potential of this aminoquinoline template as a novel scaffold to develop CXCR4 antagonists.


Assuntos
Aminoquinolinas/farmacologia , Desenho de Fármacos , Receptores CXCR4/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade
12.
J Hazard Mater ; 393: 122458, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32155526

RESUMO

As to metallosilicate zeolites, ions with larger size such as Ta5+ in the gels greatly retarded their crystallization during the hydrothermal synthesis, affording long-winded synthesis periods, up-limited framework-substituted metal contents, or even frustrated outcome. An efficient hydrothermal synthesis strategy for metallosilicate, in this case of Ta framework-substituted *BEA zeolite, via structural reconstruction was proposed to stride the gap. The Ta content in our developed Ta-Beta-Re-50 zeolite achieved up to 5.48 % (Si/Ta = 52), breaking through the limitation of Ta contents for conventional method (Si/Ta > 100). Additionally, this Ta-Beta-Re zeolite possessed nanosized crystals (20-40 nm) and short crystallization time (8 h), significantly improving space-time yields of practical zeolite production. Through spectroscopic study, it was confirmed that the existence of zeolite structural units intensively facilitated the formation of nucleation and crystal growth. This innovative Ta-Beta zeolite demonstrated high catalytic performances for oxidation desulfurization, far outperforming traditional fluoride-mediated Ta-Beta-F, which was ascribed to its excellent diffusion properties and incredible high isolated Ta contents. Additionally, the catalytic performance of Ta-Beta-Re could be regenerated after simple calcination and the deactivation may be caused by pore blocking of organics. This work provides a new method for rationally design and construction of metallosilicate materials with high activity for catalytic oxidation applications, which can bridge the conceptual and technical gap between periodic trends and zeolite material synthesis.

13.
Chem Commun (Camb) ; 56(34): 4696-4699, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32211740

RESUMO

An innovative strategy based on dual structure-directing agent-facilitated crystallization was proposed to hydrothermally synthesize boron-free Zr-MWW and Sn-MWW metallosilicates that bear great structural diversity for potential pore engineering. The metallosilicates show distinctive features in Lewis acid-catalyzed reactions as efficient heterogeneous solid catalysts.

14.
Eur J Med Chem ; 187: 111914, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806538

RESUMO

Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.


Assuntos
Pirimidinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptores CXCR4/metabolismo , Relação Estrutura-Atividade
15.
Cell Death Dis ; 10(7): 493, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235688

RESUMO

Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Necroptose/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/metabolismo , Fator de Necrose Tumoral alfa/toxicidade , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HT29 , Humanos , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Necrose/metabolismo , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Células U937
16.
Eur J Med Chem ; 172: 1-15, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30939349

RESUMO

The Hedgehog (Hh) pathway plays a critical role during embryonic development by controlling cell patterning, growth and migration. In adults, the function of Hh pathway is curtailed to tissue repair and maintenance. Aberrant reactivation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. The Smoothened (Smo) receptor, a key component of the Hh pathway which is central to the signaling transduction, has emerged as an attractive therapeutic target for the treatment of human cancers. Taking advantage of the availability of several crystal structures of Smo in complex with different antagonists, we have previously conducted a molecular docking-based virtual screening to identify several compounds which exhibited significant inhibitory activity against the Hh pathway activation (IC50 < 10 µM) in a Gli-responsive element (GRE) reporter gene assay. The most potent compound (ChemDiv ID C794-1677: 47 nM) showed comparable Hh signaling inhibition to the marketed drug vismodegib (46 nM). Herein, we report our structural optimization based on the virtual screening hit C794-1677. Our efforts are aimed to improve potency, decrease cLogP, and remove potentially metabolic labile/toxic pyrrole and aniline functionalities presented in C794-1677. The optimization led to the identification of numerous potent compounds exemplified by 25 (7.1 nM), which was 7 folds more potent compared with vismodegib. In addition, 25 was much less lipophilic compared with C794-1677 and devoid of the potentially metabolic labile/toxic pyrrole and aniline functional groups. Furthermore, 25 exhibited promising efficacy in inhibiting Gli1 mRNA expression in NIH3T3 cells with either wildtype Smo or D473H Smo mutant. These results represented significant improvement over the virtual screening hit C794-1677 and suggested that compound 25 can be used as a good starting point to support lead optimization.


Assuntos
Anilidas/farmacologia , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Piridinas/farmacologia , Receptor Smoothened/antagonistas & inibidores , Anilidas/química , Animais , Relação Dose-Resposta a Droga , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Piridinas/química , Relação Estrutura-Atividade
17.
Anticancer Drugs ; 29(10): 995-1003, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30106753

RESUMO

The hedgehog-smoothened (HH/SMO) pathway has been proposed as a potential therapeutic target for hematological malignancies. Our previous studies designed a series of HH inhibitors with novel scaffolds distinctive from vismodegib, the first Food and Drug Administration-approved HH inhibitor for the treatment of basal-cell carcinoma and medulloblastoma. In the present study, we evaluated these HH inhibitors against blood cancers and found that HH78 displayed potent activity in suppressing the HH signaling pathway. HH78 competitively bound to SMO and suppressed the transcriptional activity of GLI by the luciferase reporter gene assay and the measurement of HH/SMO-downregulated genes, including cyclin D2, cyclin E, PTCH1, PTCH2, and GLI. HH78 at low micromolar concentrations induced significant cancer cell apoptosis showed by increased caspase-3 activation, annexin V-staining and downregulated prosurvival proteins, including c-Myc, Bcl-2, Mcl-1, and Bcl-xL. In contrast, vismodegib did not show any effects on these apoptotic events. HH78 also suppressed the activation of the AKT/mTOR pathway, which cross-talks with the HH/SMO pathway. Finally, HH78 inhibited the growth of human leukemia K562 in nude mice xenografts with no overt toxicity. Collectively, the present study identified a novel HH inhibitor with great potential for the treatment of hematological malignancies.


Assuntos
Antineoplásicos/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Hematológicas/tratamento farmacológico , Receptor Smoothened/antagonistas & inibidores , Anilidas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/genética , Neoplasias Hematológicas/patologia , Humanos , Células K562 , Camundongos , Camundongos Nus , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Pharmacol Sci ; 137(3): 256-264, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30064819

RESUMO

Aberrant activation of Hedgehog (Hh) signaling is associated with the development of numerous human cancers. Vismodegib is the first Hh inhibitor approved for anti-cancer therapy by targeting Smoothened (SMO), a critical regulator of the Hh pathway. However, acquisition of drug resistance to vismodegib occurs overtime. Apoptosis is a prevalent form of programmed cell death that is executed by caspases. Induction of tumor cell apoptosis represents an attractive therapeutic strategy to eliminate tumor cells. To explore new Hh antagonists with apoptosis-inducing activity, we screened a set of ∼300 potential SMO antagonists with novel scaffold structures. Hh003 was found to induce caspase-dependent apoptosis while vismodegib did not activate apoptotic response in human colon and pancreatic cancer cells. Compared to vismodegib, Hh003 exerted similar inhibitory effects on the Hh pathway. Hh003 could induce caspase8 activation and the silence of caspase8 significantly inhibited Hh003-induced apoptosis. Remarkably, Hh003 showed stronger inhibitory effects on the formation of tumor colonies in vitro and colorectal tumor growth in vivo than vismodegib. These findings suggest that Hh003 exerts enhanced anti-tumor effects by activating caspase8-dependent apoptosis compared to vismodegib. The combined property of Hh inhibition and apoptosis induction of Hh003 presents great potential for the development of novel anti-cancer therapy.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Apoptose/genética , Caspase 8/metabolismo , Neoplasias do Colo/patologia , Proteínas Hedgehog/antagonistas & inibidores , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Terapia de Alvo Molecular , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais/fisiologia
19.
Eur J Med Chem ; 155: 34-48, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29857275

RESUMO

The Hedgehog (Hh) signaling pathway plays a critical role in controlling patterning, growth and cell migration during embryonic development. Aberrant activation of Hh signaling has been linked to tumorigenesis in various cancers, such as basal cell carcinoma (BCC) and medulloblastoma. As a key member of the Hh pathway, the Smoothened (Smo) receptor, a member of the G protein-coupled receptor (GPCR) family, has emerged as an attractive therapeutic target for the treatment and prevention of human cancers. The recent determination of several crystal structures of Smo in complex with different antagonists offers the possibility to perform structure-based virtual screening for discovering potent Smo antagonists with distinct chemical scaffolds. In this study, based on the two Smo crystal complexes with the best capacity to distinguish the known Smo antagonists from decoys, the molecular docking-based virtual screening was conducted to identify promising Smo antagonists from ChemDiv library. A total of 21 structurally novel and diverse compounds were selected for experimental testing, and six of them exhibited significant inhibitory activity against the Hh pathway activation (IC50 < 10 µM) in a GRE (Gli-responsive element) reporter gene assay. Specifically, the most potent compound (compound 20: 47 nM) showed comparable Hh signaling inhibition to vismodegib (46 nM). Compound 20 was further confirmed to be a potent Smo antagonist in a fluorescence based competitive binding assay. Optimization using substructure searching method led to the discovery of 12 analogues of compound 20 with decent Hh pathway inhibition activity, including four compounds with IC50 lower than 1 µM. The important residues uncovered by binding free energy calculation (MM/GBSA) and binding free energy decomposition were highlighted and discussed. These findings suggest that the novel scaffold afforded by compound 20 can be used as a good starting point for further modification/optimization and the clarified interaction patterns may also guide us to find more potent Smo antagonists.


Assuntos
Compostos de Boro/farmacologia , Descoberta de Drogas , Corantes Fluorescentes/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Alcaloides de Veratrum/farmacologia , Animais , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Células NIH 3T3 , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Alcaloides de Veratrum/síntese química , Alcaloides de Veratrum/química
20.
Eur J Med Chem ; 149: 30-44, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29494843

RESUMO

The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists.


Assuntos
Desenho de Fármacos , Pirimidinas/química , Receptores CXCR4/antagonistas & inibidores , Cálcio/metabolismo , Quimiocina CXCL12/fisiologia , Humanos , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
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