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1.
Drug Metab Dispos ; 49(10): 870-881, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34321251

RESUMO

Point mutations in isocitrate dehydrogenase 1 (IDH1) result in conversion of α-ketoglutarate to the oncometabolite, d-2-hydroxyglutarate (2-HG). Ivosidenib is a once daily (QD), orally available, potent, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and intensive chemotherapy-ineligible newly diagnosed AML, with a susceptible IDH1 mutation. We characterized the protein binding, metabolism, metabolites, cell permeability, and drug-drug interaction potential of ivosidenib in humans, monkeys, dogs, rats, and/or mice in in vitro experiments. In vivo pharmacokinetic (PK) profiling and assessment of drug distribution and excretion was undertaken in rats, dogs, and monkeys administered single-dose ivosidenib. The PK/pharmacodynamic (PD) relationship between ivosidenib and 2-HG was analyzed in an mIDH1 xenograft mouse model. Ivosidenib was well absorbed, showed low clearance, and moderate to long terminal half-life (5.3-18.5 hours) in rats, dogs, and monkeys. Brain to plasma exposure ratio was low (2.3%), plasma protein binding was high, and oxidative metabolism was the major elimination pathway. Ivosidenib had high cell permeability and was identified as a substrate for P-glycoprotein. There was moderate induction of cytochrome P450 (P450) enzymes CYP3A4 and CYP2B6 but minimal P450 inhibition or autoinduction. Tumor 2-HG reduction appeared to be dose- and drug-exposure-dependent. Ivosidenib showed a favorable PK profile in several animal species, along with a clear PK/PD relationship demonstrating 2-HG inhibition that translated well to patients with AML. SIGNIFICANCE STATEMENT: Ivosidenib is a mutant IDH1 (mIDH1) inhibitor approved for the treatment of certain patients with mIDH1 acute myeloid leukemia. In Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys, ivosidenib demonstrated a favorable pharmacokinetic profile, and in female BALB/c mice showed clear dose- and exposure-dependent inhibition of the oncometabolite, d-2-hydroxyglutarate, which is present at abnormal levels in mIDH1 tumors. These findings led to the further development of ivosidenib and are consistent with data from patients with mIDH1 cancers and healthy participants.


Assuntos
Glicina/análogos & derivados , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda , Piridinas/farmacocinética , Animais , Antineoplásicos/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Relação Dose-Resposta a Droga , Vias de Eliminação de Fármacos , Interações Medicamentosas , Glutaratos/metabolismo , Glicina/farmacocinética , Haplorrinos , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Ácidos Cetoglutáricos/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Taxa de Depuração Metabólica , Camundongos , Mutação Puntual , Ligação Proteica , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
2.
Toxicol Appl Pharmacol ; 401: 115103, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32522582

RESUMO

Small cell lung cancer (SCLC) is a particularly aggressive subset of lung cancer, and identification of new therapeutic options is of significant interest. We recently reported that SCLC cell lines display a specific vulnerability to inhibition of squalene epoxidase (SQLE), an enzyme in the cholesterol biosynthetic pathway that catalyzes the conversion of squalene to 2,3-oxidosqualene. Since it has been reported that SQLE inhibition can result in dermatitis in dogs, we conducted a series of experiments to determine if SQLE inhibitors would be tolerated at exposures predicted to drive maximal efficacy in SCLC tumors. Detailed profiling of the SQLE inhibitor NB-598 showed that dogs did not tolerate predicted efficacious exposures, with dose-limiting toxicity due to gastrointestinal clinical observations, although skin toxicities were also observed. To extend these studies, two SQLE inhibitors, NB-598 and Cmpd-4″, and their structurally inactive analogs, NB-598.ia and Cmpd-4″.ia, were profiled in monkeys. While both active SQLE inhibitors resulted in dose-limiting gastrointestinal toxicity, the structurally similar inactive analogs did not. Collectively, our data demonstrate that significant toxicities arise at exposures well below the predicted levels needed for anti-tumor activity. The on-target nature of the toxicities identified is likely to limit the potential therapeutic utility of SQLE inhibition for the treatment of SCLC.


Assuntos
Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/toxicidade , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Esqualeno Mono-Oxigenase/sangue , Animais , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Pele/efeitos dos fármacos , Pele/enzimologia , Pele/patologia
3.
ACS Med Chem Lett ; 11(2): 101-107, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32071674

RESUMO

Inhibitors of mutant isocitrate dehydrogenase (mIDH) 1 and 2 cancer-associated enzymes prevent the accumulation of the oncometabolite d-2-hydroxyglutarate (2-HG) and are under clinical investigation for the treatment of several cancers harboring an IDH mutation. Herein, we describe the discovery of vorasidenib (AG-881), a potent, oral, brain-penetrant dual inhibitor of both mIDH1 and mIDH2. X-ray cocrystal structures allowed us to characterize the compound binding site, leading to an understanding of the dual mutant inhibition. Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse model. Vorasidenib represents a novel dual mIDH1/2 inhibitor and is currently in clinical development for the treatment of low-grade mIDH glioma.

4.
Nat Commun ; 10(1): 97, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626872

RESUMO

Squalene epoxidase (SQLE), also known as squalene monooxygenase, catalyzes the stereospecific conversion of squalene to 2,3(S)-oxidosqualene, a key step in cholesterol biosynthesis. SQLE inhibition is targeted for the treatment of hypercholesteremia, cancer, and fungal infections. However, lack of structure-function understanding has hindered further progression of its inhibitors. We have determined the first three-dimensional high-resolution crystal structures of human SQLE catalytic domain with small molecule inhibitors (2.3 Å and 2.5 Å). Comparison with its unliganded state (3.0 Å) reveals conformational rearrangements upon inhibitor binding, thus allowing deeper interpretation of known structure-activity relationships. We use the human SQLE structure to further understand the specificity of terbinafine, an approved agent targeting fungal SQLE, and to provide the structural insights into terbinafine-resistant mutants encountered in the clinic. Collectively, these findings elucidate the structural basis for the specificity of the epoxidation reaction catalyzed by SQLE and enable further rational development of next-generation inhibitors.


Assuntos
Esqualeno Mono-Oxigenase/química , Esqualeno Mono-Oxigenase/metabolismo , Animais , Domínio Catalítico , Linhagem Celular , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Insetos , Conformação Proteica , Domínios Proteicos , Esqualeno/metabolismo , Esqualeno Mono-Oxigenase/antagonistas & inibidores
5.
Nat Commun ; 10(1): 96, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30626880

RESUMO

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Esqualeno Mono-Oxigenase/antagonistas & inibidores , Esqualeno Mono-Oxigenase/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Colesterol/biossíntese , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos
6.
ACS Med Chem Lett ; 9(4): 300-305, 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29670690

RESUMO

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

7.
Blood ; 130(11): 1347-1356, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28760888

RESUMO

Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.


Assuntos
Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Eritrócitos/enzimologia , Piruvato Quinase/deficiência , Piruvato Quinase/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Anemia Hemolítica Congênita não Esferocítica , Animais , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/química , Eritrócitos/efeitos dos fármacos , Humanos , Cinética , Camundongos , Piperazinas , Piruvato Quinase/efeitos dos fármacos , Erros Inatos do Metabolismo dos Piruvatos , Quinolinas/química , Proteínas Recombinantes/metabolismo , Sulfonamidas/química , Doadores de Tecidos
10.
Nature ; 513(7516): 110-4, 2014 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-25043045

RESUMO

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Diferenciação Celular/genética , Colangiocarcinoma/patologia , Fator 4 Nuclear de Hepatócito/antagonistas & inibidores , Hepatócitos/patologia , Isocitrato Desidrogenase/genética , Proteínas Mutantes/metabolismo , Animais , Neoplasias dos Ductos Biliares/enzimologia , Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos/enzimologia , Ductos Biliares Intra-Hepáticos/patologia , Divisão Celular/genética , Linhagem da Célula/genética , Colangiocarcinoma/enzimologia , Colangiocarcinoma/genética , Modelos Animais de Doenças , Feminino , Glutaratos/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Mutantes/genética , Mutação/genética , Metástase Neoplásica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Células-Tronco/patologia , Proteínas ras/genética , Proteínas ras/metabolismo
11.
Bioorg Med Chem ; 22(7): 2303-10, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24588962

RESUMO

The ribonucleotide reductase (RNR) enzyme is a heteromer of RRM1 and RRM2 subunits. The active enzyme catalyzes de novo reduction of ribonucleotides to generate deoxyribonucleotides (dNTPs), which are required for DNA replication and DNA repair processes. Complexity in the generation of physiologically relevant, active RRM1/RRM2 heterodimers was perceived as limiting to the identification of selective RRM1 inhibitors by high-throughput screening of compound libraries and led us to seek alternative methods to identify lead series. In short, we found that gemcitabine, as its diphosphate metabolite, represents one of the few described active site inhibitors of RRM1. We herein describe the identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors through in-cell phenotypic screening.


Assuntos
Desoxicitidina/análogos & derivados , Proteínas Supressoras de Tumor/antagonistas & inibidores , Linhagem Celular Tumoral , Desoxicitidina/química , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ribonucleosídeo Difosfato Redutase , Relação Estrutura-Atividade , Gencitabina
12.
J Biol Chem ; 289(20): 13717-25, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24668804

RESUMO

Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 µm) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 µm). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to α-ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.


Assuntos
Acetamidas/farmacologia , Benzimidazóis/farmacologia , Fenômenos Biofísicos , Inibidores Enzimáticos/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/genética , Mutação , Acetamidas/metabolismo , Acetamidas/farmacocinética , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos , Proteínas Mutantes/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Bioorg Med Chem Lett ; 24(1): 199-203, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24332088

RESUMO

A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005µM.


Assuntos
Ciclina A/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Cristalografia por Raios X , Ciclina A/química , Ciclina A/metabolismo , Quinase 2 Dependente de Ciclina/química , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/química , Relação Estrutura-Atividade
14.
Science ; 340(6132): 626-30, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23558169

RESUMO

The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.


Assuntos
Benzenoacetamidas/farmacologia , Diferenciação Celular , Inibidores Enzimáticos/farmacologia , Glioma/enzimologia , Glioma/patologia , Imidazóis/farmacologia , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Animais , Benzenoacetamidas/administração & dosagem , Benzenoacetamidas/toxicidade , Diferenciação Celular/efeitos dos fármacos , Transformação Celular Neoplásica , Inibidores Enzimáticos/toxicidade , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Glutaratos/metabolismo , Histonas/metabolismo , Imidazóis/administração & dosagem , Imidazóis/toxicidade , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/metabolismo , Metilação , Camundongos , Camundongos SCID , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Multimerização Proteica , Interferência de RNA , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Science ; 340(6132): 622-6, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23558173

RESUMO

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.


Assuntos
Inibidores Enzimáticos/farmacologia , Hematopoese/efeitos dos fármacos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/enzimologia , Compostos de Fenilureia/farmacologia , Sulfonamidas/farmacologia , Sítio Alostérico , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Eritropoese/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica , Glutaratos/metabolismo , Humanos , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/metabolismo , Leucemia Eritroblástica Aguda , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Terapia de Alvo Molecular , Proteínas Mutantes/antagonistas & inibidores , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Mutação Puntual , Multimerização Proteica , Estrutura Secundária de Proteína , Bibliotecas de Moléculas Pequenas , Sulfonamidas/química , Sulfonamidas/metabolismo
16.
ACS Med Chem Lett ; 3(10): 850-5, 2012 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-24900389

RESUMO

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

17.
Bioorg Med Chem Lett ; 21(10): 3172-6, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21458257

RESUMO

TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to zinc in a unique tridentate fashion. Incorporating (R)-2-(2-N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Amidas/farmacologia , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Tartaratos/química , Proteína ADAM17 , Amidas/síntese química , Amidas/química , Animais , Disponibilidade Biológica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Ratos
18.
Bioorg Med Chem Lett ; 20(24): 7283-7, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21106451

RESUMO

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/química , Artrite Reumatoide/tratamento farmacológico , Inibidores de Proteases/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Cães , Haplorrinos , Humanos , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Ratos
20.
Bioorg Med Chem Lett ; 20(6): 1877-80, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20172725

RESUMO

We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hidantoínas/farmacologia , Proteína ADAM17 , Inibidores Enzimáticos/química , Hidantoínas/química , Ligação de Hidrogênio , Modelos Moleculares , Relação Estrutura-Atividade , Difração de Raios X
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