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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.
Cancer Cell ; 5(1): 91-102, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14749129

RESUMO

Key molecular lesions in colorectal and other cancers cause beta-catenin-dependent transactivation of T cell factor (Tcf)-dependent genes. Disruption of this signal represents an opportunity for rational cancer therapy. To identify compounds that inhibit association between Tcf4 and beta-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/beta-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of beta-catenin-dependent activities, including reporter gene activation, c-myc or cyclin D1 expression, cell proliferation, and duplication of the Xenopus embryonic dorsal axis. These compounds thus meet predicted criteria for disrupting Tcf/beta-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/metabolismo , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Células COS , Divisão Celular/fisiologia , Chlorocebus aethiops , Técnicas de Química Combinatória , Ciclina D1/metabolismo , Ligação Proteica , Ressonância de Plasmônio de Superfície , Xenopus/metabolismo , Proteínas de Xenopus , beta Catenina
3.
Nature ; 441(7092): 451-6, 2006 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-16724057

RESUMO

A cancer drug target is only truly validated by demonstrating that a given therapeutic agent is clinically effective and acts through the target against which it was designed. Nevertheless, it is desirable to declare an early-stage drug target as 'validated' before investing in a full-scale drug discovery programme dedicated to it. Although the outcome of validation studies can guide cancer research programmes, strictly defined universal validation criteria have not been established.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Células/efeitos dos fármacos , Células/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Neoplasias/genética , Neoplasias/patologia , Reprodutibilidade dos Testes , Especificidade por Substrato
4.
Cell Chem Biol ; 27(12): 1500-1509.e13, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-32888499

RESUMO

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteólise/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos
5.
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
6.
Org Lett ; 11(3): 737-40, 2009 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-19175352

RESUMO

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Depsipeptídeos/síntese química , Depsipeptídeos/farmacologia , Fatores de Transcrição E2F/metabolismo , Fatores de Transcrição/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Antineoplásicos/química , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Depsipeptídeos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Transcrição E2F1/metabolismo , Humanos , Concentração Inibidora 50 , Fator de Transcrição 4
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