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1.
J Biol Chem ; 294(49): 18522-18531, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31578280

RESUMO

Cytokine macrophage migration inhibitory factor-2 (MIF-2 or D-dopachrome tautomerase) is a recently characterized second member of the MIF cytokine superfamily in mammalian genomes. MIF-2 shares pro-inflammatory and tumorigenic properties with the clinical target MIF (MIF-1), but the precise contribution of MIF-2 to immune physiology or pathology is unclear. Like MIF-1, MIF-2 has intrinsic keto-enol tautomerase activity and mediates biological functions by engaging the cognate, common MIF family receptor CD74. Evidence that the catalytic site of MIF family cytokines has a structural role in receptor binding has prompted exploration of tautomerase inhibitors as potential biological antagonists and therapeutic agents, although few catalytic inhibitors inhibit receptor activation. Here we describe the discovery and biochemical characterization of a selective small-molecule inhibitor of MIF-2. An in silico screen of 1.6 million compounds targeting the MIF-2 tautomerase site yielded several hits for potential catalytic inhibitors of MIF-2 and identified 4-(3-carboxyphenyl)-2,5-pyridinedicarboxylic acid (4-CPPC) as the most functionally potent compound. We found that 4-CPPC has an enzymatic IC50 of 27 µm and 17-fold selectivity for MIF-2 versus MIF-1. An in vitro binding assay for MIF-1/MIF-2 to the CD74 ectodomain (sCD74) indicated that 4-CPPC inhibits MIF-2-CD74 binding in a dose-dependent manner (0.01-10 µm) without influencing MIF-1-CD74 binding. Notably, 4-CPPC inhibited MIF-2-mediated activation of CD74 and reduced CD74-dependent signal transduction. These results open opportunities for development of more potent and pharmacologically auspicious MIF-2 inhibitors to investigate the distinct functions of this MIF family member in vivo.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Hormônio Inibidor da Liberação de MSH/metabolismo , Humanos , Inflamação/enzimologia , Inflamação/metabolismo , Oxirredutases Intramoleculares/química , Hormônio Inibidor da Liberação de MSH/química , Neoplasias/enzimologia , Neoplasias/metabolismo , Estrutura Secundária de Proteína , Transdução de Sinais
2.
Clin Cancer Res ; 30(16): 3549-3563, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38819400

RESUMO

PURPOSE: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI). RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib. CONCLUSIONS: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Transdução de Sinais , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Feminino , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/antagonistas & inibidores , Piperazinas/farmacologia , Piperazinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Receptores de Estrogênio/metabolismo , Piridinas/administração & dosagem , Piridinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proliferação de Células/efeitos dos fármacos
3.
Bioorg Med Chem Lett ; 23(7): 2027-30, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23453840

RESUMO

Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.


Assuntos
Aminocaproatos/farmacologia , Arginase/antagonistas & inibidores , Compostos de Boro/farmacologia , Inibidores Enzimáticos/farmacologia , Aminocaproatos/síntese química , Aminocaproatos/química , Arginase/metabolismo , Compostos de Boro/síntese química , Compostos de Boro/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 23(17): 4837-41, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23886684

RESUMO

The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date.


Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Aminocaproatos/química , Aminocaproatos/farmacologia , Arginase/antagonistas & inibidores , Compostos de Boro/química , Compostos de Boro/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Aminoácidos/síntese química , Aminocaproatos/síntese química , Arginase/metabolismo , Compostos de Boro/síntese química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
5.
J Med Chem ; 56(6): 2568-80, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23472952

RESUMO

Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II.


Assuntos
Aminoácidos/química , Aminoácidos/farmacologia , Arginase/antagonistas & inibidores , Compostos de Boro/química , Compostos de Boro/farmacologia , Caproatos/química , Caproatos/farmacologia , Descoberta de Drogas , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Aminoácidos/farmacocinética , Aminoácidos/uso terapêutico , Animais , Arginase/química , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Células CHO , Caproatos/farmacocinética , Caproatos/uso terapêutico , Cricetinae , Cricetulus , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Masculino , Modelos Moleculares , Conformação Proteica , Ratos , Relação Estrutura-Atividade
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