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1.
Nucleic Acids Res ; 51(D1): D358-D367, 2023 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-36370112

RESUMO

Antibodies are ubiquitous key biological research resources yet are tricky to use as they are prone to performance issues and represent a major source of variability across studies. Understanding what antibody was used in a published study is therefore necessary to repeat and/or interpret a given study. However, antibody reagents are still frequently not cited with sufficient detail to determine which antibody was used in experiments. The Antibody Registry is a public, open database that enables citation of antibodies by providing a persistent record for any antibody-based reagent used in a publication. The registry is the authority for antibody Research Resource Identifiers, or RRIDs, which are requested or required by hundreds of journals seeking to improve the citation of these key resources. The registry is the most comprehensive listing of persistently identified antibody reagents used in the scientific literature. Data contributors span individual authors who use antibodies to antibody companies, which provide their entire catalogs including discontinued items. Unlike many commercial antibody listing sites which tend to remove reagents no longer sold, registry records persist, providing an interface between a fast-moving commercial marketplace and the static scientific literature. The Antibody Registry (RRID:SCR_006397) https://antibodyregistry.org.


Assuntos
Anticorpos , Bases de Dados Factuais , Sistema de Registros
2.
J Med Chem ; 64(1): 644-661, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356246

RESUMO

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.


Assuntos
Desenho de Fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão/métodos , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Ratos , Espectrometria de Massas por Ionização por Electrospray/métodos
3.
J Med Chem ; 60(7): 3002-3019, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28287730

RESUMO

Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.


Assuntos
Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Acrilamidas/química , Acrilamidas/farmacocinética , Acrilamidas/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cães , Halogenação , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases/farmacocinética , Pirrolidinas/farmacocinética , Ratos
4.
J Med Chem ; 59(5): 2005-24, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26756222

RESUMO

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.


Assuntos
Descoberta de Drogas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Proteínas Mutantes/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Modelos Moleculares , Estrutura Molecular , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
5.
Bioorg Med Chem Lett ; 23(11): 3358-63, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23622982

RESUMO

The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.


Assuntos
Benzimidazóis/química , Proteínas de Transporte/agonistas , Proteínas de Membrana/agonistas , Pirimidinonas/química , Hormônios Tireóideos/agonistas , Sítios de Ligação , Proteínas de Transporte/metabolismo , Linhagem Celular , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Cinética , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Relação Estrutura-Atividade , Hormônios Tireóideos/metabolismo , Proteínas de Ligação a Hormônio da Tireoide
6.
Bioorg Med Chem Lett ; 23(9): 2787-92, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23506825

RESUMO

PI3K, AKT and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.


Assuntos
Antineoplásicos/química , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Pirimidinonas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Camundongos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/síntese química , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridonas/química , Pirimidinas/química , Pirimidinonas/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Bioorg Med Chem Lett ; 22(24): 7605-9, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23116892

RESUMO

(S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.


Assuntos
Aminopiridinas/química , Aminopiridinas/metabolismo , Elétrons , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Mutagenicidade , Oxirredução , Fatores de Tempo
8.
J Med Chem ; 55(18): 8091-109, 2012 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-22924734

RESUMO

The c-MET receptor tyrosine kinase is an attractive oncology target because of its critical role in human oncogenesis and tumor progression. An oxindole hydrazide hit 6 was identified during a c-MET HTS campaign and subsequently demonstrated to have an unusual degree of selectivity against a broad array of other kinases. The cocrystal structure of the related oxindole hydrazide c-MET inhibitor 10 with a nonphosphorylated c-MET kinase domain revealed a unique binding mode associated with the exquisite selectivity profile. The chemically labile oxindole hydrazide scaffold was replaced with a chemically and metabolically stable triazolopyrazine scaffold using structure based drug design. Medicinal chemistry lead optimization produced 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (2, PF-04217903), an extremely potent and exquisitely selective c-MET inhibitor. 2 demonstrated effective tumor growth inhibition in c-MET dependent tumor models with good oral PK properties and an acceptable safety profile in preclinical studies. 2 progressed to clinical evaluation in a Phase I oncology setting.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazinas/farmacologia , Triazóis/farmacologia , Sequência de Aminoácidos , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Indóis/química , Modelos Moleculares , Dados de Sequência Molecular , Oxindóis , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazinas/química , Pirazinas/metabolismo , Especificidade por Substrato , Triazóis/química , Triazóis/metabolismo
9.
Bioorg Med Chem Lett ; 22(7): 2572-8, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22377517

RESUMO

Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.


Assuntos
Antagonistas de Receptores de Andrógenos/síntese química , Antineoplásicos/síntese química , Benzimidazóis/síntese química , Indóis/síntese química , Receptores Androgênicos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/farmacologia , Ligantes , Masculino , Modelos Moleculares , Neoplasias da Próstata , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores Androgênicos/metabolismo , Solubilidade , Relação Estrutura-Atividade
10.
Bioorg Med Chem Lett ; 22(2): 1230-6, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22197140

RESUMO

High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.


Assuntos
Descoberta de Drogas , Lactamas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/química , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Lactamas/síntese química , Lactamas/química , Masculino , Modelos Moleculares , Estrutura Molecular , Neoplasias da Próstata/cirurgia , Receptores Androgênicos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
11.
J Med Chem ; 54(21): 7693-704, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21936524

RESUMO

An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.


Assuntos
Antagonistas de Androgênios/síntese química , Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclobutanos/síntese química , Pirazóis/síntese química , Administração Oral , Antagonistas de Androgênios/farmacocinética , Antagonistas de Androgênios/farmacologia , Androgênios/síntese química , Androgênios/farmacocinética , Androgênios/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Ciclobutanos/farmacocinética , Ciclobutanos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Pirazóis/farmacocinética , Pirazóis/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Med Chem ; 54(21): 7705-12, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21955208

RESUMO

N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}imidazo[1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.


Assuntos
Aldeído Oxidase/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclobutanos/química , Imidazóis/química , Pirimidinas/química , Aldeído Oxidase/metabolismo , Domínio Catalítico , Humanos , Imidazóis/síntese química , Imidazóis/metabolismo , Modelos Moleculares , Oxirredução , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
13.
J Med Chem ; 54(18): 6342-63, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21812414

RESUMO

Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.


Assuntos
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirazóis/síntese química , Piridinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Transição Epitelial-Mesenquimal , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Conformação Molecular , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
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