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1.
Nature ; 535(7610): 148-52, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27362227

RESUMO

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/patologia , Proteína Oncogênica p21(ras)/metabolismo , Piperidinas/química , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/química , Pirimidinas/uso terapêutico , Reprodutibilidade dos Testes , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Org Chem ; 86(23): 17428-17436, 2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34808052

RESUMO

Facilitating photoredox coupling reactions in process-friendly green solvents was achieved by the successful application of a dual Ir/Ni catalyst system with enhanced solubility properties. These photochemical reactions (specifically Br-Br sp2-sp3 cross electrophile coupling) are reported in a head to head comparison to the standard di-t-Bu bipyridine ligand Ir/Ni catalyst system. This presentation highlights the benefits of altering the solubility properties of the ligands used in the Ir/Ni dual catalyst.


Assuntos
Níquel , Catálise , Ligantes , Oxirredução , Solventes
3.
J Med Chem ; 63(22): 13578-13594, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32910655

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/uso terapêutico , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Macaca fascicularis , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Ratos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
5.
ACS Chem Biol ; 13(3): 647-656, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29304282

RESUMO

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (2) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that 2 binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding site-a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.


Assuntos
Regulação Alostérica , Sítio Alostérico , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/tratamento farmacológico , Conformação Proteica , Estabilidade Proteica
6.
J Med Chem ; 50(5): 984-1000, 2007 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-17274610

RESUMO

Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.


Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Indanos/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Triazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Apolipoproteína A-I/genética , Linhagem Celular , Cricetinae , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Indanos/química , Indanos/farmacologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/genética , PPAR gama/genética , Ensaio Radioligante , Ratos , Ratos Zucker , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triazóis/química , Triazóis/farmacologia
7.
J Med Chem ; 59(17): 7773-82, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27347692

RESUMO

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.


Assuntos
Antineoplásicos/química , Piperidinas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirazinas/química , Pirimidinas/química , Administração Oral , Regulação Alostérica , Sítio Alostérico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Xenoenxertos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Piperidinas/síntese química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Relação Estrutura-Atividade
8.
J Med Chem ; 56(17): 7049-59, 2013 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-23879431

RESUMO

Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, herein we report the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members. We demonstrate the utilization of lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive the evaluation of this series. These efforts led to a series of selective, cell-active compounds with solubility, physicochemical, and in vitro properties suitable for further optimization.


Assuntos
Aminas/farmacologia , Tanquirases/antagonistas & inibidores , Triazóis/farmacologia , Aminas/química , Animais , Ensaio de Imunoadsorção Enzimática , Masculino , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/química
9.
J Med Chem ; 56(16): 6495-511, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23844574

RESUMO

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.


Assuntos
Acetamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirimidinonas/farmacologia , Tanquirases/antagonistas & inibidores , Acetamidas/administração & dosagem , Acetamidas/química , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Inibidores Enzimáticos/administração & dosagem , Camundongos , Modelos Moleculares , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Relação Estrutura-Atividade
10.
J Med Chem ; 54(13): 4752-72, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21650221

RESUMO

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.


Assuntos
Acrilamidas/toxicidade , Antineoplásicos/toxicidade , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Inibidores de Histona Desacetilases/toxicidade , Ácidos Hidroxâmicos/toxicidade , Acrilamidas/síntese química , Acrilamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Canal de Potássio ERG1 , Células HCT116 , Meia-Vida , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Transplante de Neoplasias , Técnicas de Patch-Clamp , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante Heterólogo
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