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1.
Annu Rev Biochem ; 86: 305-331, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28375741

RESUMO

The identification of heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) in subsets of cancers, including secondary glioblastoma, acute myeloid leukemia, intrahepatic cholangiocarcinoma, and chondrosarcomas, led to intense discovery efforts to delineate the mutations' involvement in carcinogenesis and to develop therapeutics, which we review here. The three IDH isoforms (nicotinamide adenine dinucleotide phosphate-dependent IDH1 and IDH2, and nicotinamide adenine dinucleotide-dependent IDH3) contribute to regulating the circuitry of central metabolism. Several biochemical and genetic observations led to the discovery of the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate (2-HG) by mutant IDH1 and IDH2 (mIDH). Heterozygous mutation of IDH1/2 and accumulation of 2-HG cause profound metabolic and epigenetic dysregulation, including inhibition of normal cellular differentiation, leading to disease. Crystallographic structural studies during the development of compounds targeting mIDH demonstrated common allosteric inhibition by distinct chemotypes. Ongoing clinical trials in patients with mIDH advanced hematologic malignancies have demonstrated compelling clinical proof-of-concept, validating the biology and drug discovery approach.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Glutaratos/metabolismo , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Acetamidas/síntese química , Acetamidas/uso terapêutico , Antineoplásicos/síntese química , Benzenoacetamidas/síntese química , Benzenoacetamidas/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Biomarcadores Tumorais/análise , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Expressão Gênica , Glutaratos/análise , Humanos , Imidazóis/síntese química , Imidazóis/uso terapêutico , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Modelos Moleculares , Mutação , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Pesquisa Translacional Biomédica
2.
Mol Cell ; 81(11): 2278-2289, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33984284

RESUMO

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Reparo do DNA/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/tratamento farmacológico , Ubiquitina-Proteína Ligases/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Dano ao DNA , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/antagonistas & inibidores , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Morfolinas/uso terapêutico , Pironas/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/antagonistas & inibidores , Ubiquitinas/genética , Ubiquitinas/metabolismo
3.
RNA ; 30(9): 1213-1226, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-38918043

RESUMO

Telomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α-primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerase in vitro, and in human cells they cause telomere shortening that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these "telomerase inhibitors" indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their binding to GQ RNA and their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells.


Assuntos
Inibidores Enzimáticos , Quadruplex G , Telomerase , Telômero , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Telomerase/genética , Humanos , Telômero/metabolismo , Quadruplex G/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Ácidos Picolínicos/farmacologia , Ácidos Picolínicos/química , Replicação do DNA/efeitos dos fármacos , DNA Polimerase I/antagonistas & inibidores , DNA Polimerase I/metabolismo , DNA/metabolismo , Aminoquinolinas , Porfirinas , DNA Primase
4.
Glycobiology ; 34(11)2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39088577

RESUMO

The prevalent human pathogen, mumps virus (MuV; orthorubulavirus parotitidis) causes various complications and serious sequelae, such as meningitis, encephalitis, deafness, and impaired fertility. Direct-acting antivirals (DAAs) targeting MuV which can prevent mumps and mumps-associated complications and sequelae are yet to be developed. Paramyxoviridae family members, such as MuV, possess viral surface hemagglutinin-neuraminidase (HN) protein with sialidase activity which facilitates efficient viral replication. Therefore, to develop DAAs targeting MuV we synthesized MuV sialidase inhibitors. It is proposed that the viral HN has a single functional site for N-acetylneuraminic acid (Neu5Ac) binding and sialidase activity. Further, the known MuV sialidase inhibitor is an analog of Neu5Ac-2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA)-which lacks potency. DANA derivatives with higher MuV sialidase inhibitory potency are lacking. The MuV-HN-Neu5Ac binding site has a hydrophobic cavity adjacent to the C4 position of Neu5Ac. Exploiting this, here, we synthesized DANA derivatives with increasing hydrophobicity at its C4 position and created 3 novel sialidase inhibitors (Compounds 1, 2, and 3) with higher specificity for MuV-HN than DANA; they inhibited MuV replication step to greater extent than DANA. Furthermore, they also inhibited hemagglutination and the MuV infection step. The insight-that these 3 novel DANA derivatives possess linear hydrocarbon groups at the C4-hydroxyl group of DANA-could help develop highly potent sialidase inhibitors with high specificity for MuV sialidase, which may function as direct-acting MuV-specific antivirals.


Assuntos
Antivirais , Vírus da Caxumba , Neuraminidase , Replicação Viral , Vírus da Caxumba/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Animais , Chlorocebus aethiops , Proteína HN/metabolismo , Proteína HN/química , Células Vero , Caxumba/tratamento farmacológico , Caxumba/virologia
5.
J Am Chem Soc ; 146(29): 20370-20378, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-38981108

RESUMO

The antibiotic cerulenin is a fungal natural product identified as a covalent inhibitor of ketosynthases within fatty acid and polyketide biosynthesis. Due to its selective and potent inhibitory activity, cerulenin has found significant utility in multidisciplinary biochemical, biomedical, and clinical studies. Although its covalent inhibition profile has been confirmed, cerulenin's mechanism has not been fully determined at a molecular level, frustrating the drug development of related analogues. Herein, we describe the use of stable isotopic tracking with NMR and MS methods to unravel the covalent mechanism of cerulenin against type II fatty acid ketosynthases. We detail the discovery of a unique C2-C3 retro-aldol bond cleavage and a structural rearrangement upon covalent inhibition of cerulenin at the active cysteine residue in E. coli type II fatty acid ketosynthases FabB and FabF.


Assuntos
Cerulenina , Cerulenina/farmacologia , Cerulenina/química , Escherichia coli/enzimologia , Escherichia coli/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/metabolismo , Modelos Moleculares , Estrutura Molecular
6.
J Am Chem Soc ; 146(28): 18967-18978, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38973592

RESUMO

Platensilin, platensimycin, and platencin are potent inhibitors of ß-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent-pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent-pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent-pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC80 = 0.0625 µg/mL) against S. aureus compared to platensimycin.


Assuntos
Adamantano , Aminobenzoatos , Aminofenóis , Anilidas , Compostos Policíclicos , Aminofenóis/química , Aminofenóis/farmacologia , Aminofenóis/síntese química , Compostos Policíclicos/química , Compostos Policíclicos/farmacologia , Compostos Policíclicos/síntese química , Adamantano/química , Adamantano/farmacologia , Adamantano/síntese química , Adamantano/análogos & derivados , Anilidas/farmacologia , Anilidas/química , Anilidas/síntese química , Aminobenzoatos/farmacologia , Aminobenzoatos/química , Aminobenzoatos/síntese química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Staphylococcus aureus/efeitos dos fármacos , Estrutura Molecular , Reação de Cicloadição , Testes de Sensibilidade Microbiana , Estereoisomerismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química
7.
Chembiochem ; 25(12): e202400235, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38642076

RESUMO

The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT-1 cells, and X-ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L-DOPA, namely (S)-3-amino-tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.


Assuntos
Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Fenilalanina , Humanos , Monofenol Mono-Oxigenase/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Fenilalanina/química , Fenilalanina/metabolismo , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Cristalografia por Raios X , Simulação de Dinâmica Molecular , Domínio Catalítico , Estrutura Molecular
8.
J Org Chem ; 89(12): 9098-9102, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38861461

RESUMO

We report the first total synthesis of scleropentaside D, a unique C-glycosidic ellagitannin, from the ketal derivative of scleropentaside A employing site-selective O4-protection of C-acyl glycoside and copper-catalyzed oxidative coupling reaction of galloyl groups as the key steps. Our study confirms the proposed structure of this natural product, scleropentaside D, and demonstrates its effectiveness as an inhibitor of α-glycosidase.


Assuntos
Taninos Hidrolisáveis , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/farmacologia , Taninos Hidrolisáveis/síntese química , Estrutura Molecular , Glicosídeos/química , Glicosídeos/síntese química , Glicosídeos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Catálise
9.
J Org Chem ; 89(20): 14650-14657, 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-38720168

RESUMO

Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.


Assuntos
Compostos de Boro , Carboxilesterase , Inibidores Enzimáticos , Corantes Fluorescentes , Ensaios de Triagem em Larga Escala , Humanos , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Ensaios de Triagem em Larga Escala/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Compostos de Boro/química , Compostos de Boro/farmacologia , Carboxilesterase/antagonistas & inibidores , Carboxilesterase/metabolismo , Carboxilesterase/análise , Desenho de Fármacos , Estrutura Molecular
10.
Bioorg Med Chem Lett ; 109: 129823, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38823727

RESUMO

The tyrosinase (TYR) enzyme catalyses sequential reactions in the melanogenesis pathway: l-tyrosine is oxidised to yield L-3,4-dihydroxyphenylalanine (l-dopa), which in turn is converted to dopaquinone. These two reactions are the first two steps of melanin biosynthesis and are rate limiting. The accumulation or overproduction of melanin may cause skin hyperpigmentation and inhibitors of TYR are thus of interest to the cosmeceutical industry. Several TYR inhibitors are used to treat skin hyperpigmentation, however, some are ineffective and possess questionable safety profiles. This emphasises the need to develop novel TYR inhibitors with better safety and efficacy profiles. The small molecule, 3-hydroxycoumarin, has been reported to be a good potency TYR inhibitor (IC50 = 2.49 µM), and based on this, a series of eight structurally related 3-hydroxyquinolin-2(1H)-one derivatives were synthesised with the aim to discover novel TYR inhibitors. The results showed that four of the derivatives inhibited TYR from the champignon mushroom Agaricus bisporus (abTYR) with IC50 < 6.11 µM. The most potent inhibitor displayed an IC50 value of 2.52 µM. Under the same conditions, the reference inhibitors, thiamidol and kojic acid, inhibited abTYR with IC50 values of 0.130 and 26.4 µM, respectively. Based on the small molecular structures of the active 3-hydroxyquinolin-2(1H)-one inhibitors which are amenable to structure optimisation, it may be concluded that this class of compounds are good leads for the design of TYR inhibitors for cosmeceutical applications.


Assuntos
Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Relação Estrutura-Atividade , Estrutura Molecular , Agaricus/enzimologia , Relação Dose-Resposta a Droga
11.
Bioorg Med Chem Lett ; 110: 129820, 2024 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851358

RESUMO

The STING (stimulator of interferon genes) pathway is one of the pathways that regulate innate immunity, and the extracellular hydrolytic enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as its dominant negative regulator. Since activation of the innate immune system is a promising strategy for the treatment of various infectious diseases and cancers, ENPP1 inhibitors have attracted great attention as candidate drugs. We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems.


Assuntos
Diester Fosfórico Hidrolases , Pirimidinas , Pirofosfatases , Relação Estrutura-Atividade , Diester Fosfórico Hidrolases/metabolismo , Humanos , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirofosfatases/antagonistas & inibidores , Pirofosfatases/metabolismo , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química
12.
Bioorg Med Chem Lett ; 112: 129930, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39179180

RESUMO

Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer's virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.


Assuntos
Disponibilidade Biológica , Inibidores Enzimáticos , Frutoquinases , Animais , Frutoquinases/antagonistas & inibidores , Frutoquinases/metabolismo , Ratos , Administração Oral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Relação Estrutura-Atividade , Descoberta de Drogas , Estrutura Molecular , Relação Dose-Resposta a Droga
13.
Bioorg Med Chem Lett ; 106: 129731, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38621594

RESUMO

The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure-activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.


Assuntos
Hidroxilamina , Indolamina-Pirrol 2,3,-Dioxigenase , Cinurenina , Cinurenina/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Relação Estrutura-Atividade , Humanos , Hidroxilamina/química , Hidroxilamina/farmacologia , Hidroxilaminas/química , Hidroxilaminas/farmacologia , Estrutura Molecular , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Relação Dose-Resposta a Droga
14.
Bioorg Med Chem Lett ; 113: 129948, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39236793

RESUMO

KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER+ breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.


Assuntos
Inibidores Enzimáticos , Histona Acetiltransferases , Triazóis , Humanos , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Benzenossulfonamidas
15.
Bioorg Med Chem Lett ; 113: 129965, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39284456

RESUMO

DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound 3 (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core. The correct positioning of the nitrogen in these core systems proved to be essential in modulating potency. Herein is described the synthesis of these complexly functionalized cores and their profiling, leading to DHODH inhibitors that possess favorable properties suitable for further development.


Assuntos
Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/síntese química , Cristalografia por Raios X , Animais , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Relação Dose-Resposta a Droga
16.
Bioorg Med Chem Lett ; 113: 129975, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39332648

RESUMO

Arylalkylamine N-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.


Assuntos
Arilalquilamina N-Acetiltransferase , Triptaminas , Triptaminas/química , Triptaminas/metabolismo , Triptaminas/síntese química , Cinética , Arilalquilamina N-Acetiltransferase/metabolismo , Arilalquilamina N-Acetiltransferase/química , Humanos , Relação Estrutura-Atividade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga
17.
Bioorg Med Chem Lett ; 113: 129976, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39332649

RESUMO

Inhibition of tyrosinase by gallic acid, epigallocatechin, and epigallocatechin-3-gallate has been recently described in several publications. However, oxidation of these compounds by this enzyme was demonstrated long time ago. Gallic acid also reduced tyrosinase-generated o-quinones. We have shown that epigallocatechin and epigallocatechin-3-gallate are also rapidly oxidized by o-quinones generated from catechols by tyrosinase or by treatment with sodium periodate. Smaller changes of absorbance at 475 nm during oxidation of l-dopa in the presence of gallic acid, epigallocatechin, and epigallocatechin-3-gallate result from reduction of dopaquinone by these compounds. This reaction prevents formation of dopachrome giving an effect of inhibition, which is only apparent. The actual reaction rates measured by oxygen consumption did not decrease in the presence of these compounds. The standard spectrophotometric assay cannot therefore be used to monitor tyrosinase activity with compounds possessing strong reducing properties, particularly flavonoids, because their influence on dopachrome formation does not result from inhibition of this enzyme. Such compounds should be considered antimelanogenic or antibrowning agents.


Assuntos
Catequina , Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Oxirredução , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química
18.
Bioorg Med Chem Lett ; 112: 129946, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39226996

RESUMO

High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for cancer immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC50 values of 0.28 µM and 0.10 µM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.


Assuntos
5'-Nucleotidase , Desenho de Fármacos , Inibidores Enzimáticos , Malonatos , Relação Estrutura-Atividade , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Humanos , Malonatos/química , Malonatos/farmacologia , Malonatos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo
19.
Bioorg Med Chem Lett ; 112: 129931, 2024 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-39154713

RESUMO

Methionine aminopeptidase (MetAp) enzymes catalyze the post-translational removal of the initiator methionine residue in newly synthesized proteins, a process that is often essential in the maturation of proteins. Consequently, these enzymes serve as important targets for drug development. Rickettsia prowazekii (Rp) is an obligate coccobacillus and the causative agent of the louse-borne epidemic typhus and despite adequate treatment causes a latent infection. This research aimed to identify potential anti-rickettsial agents by screening 400 compounds from the MMV Pandemic Response Box against RpMetAp1. Overall, 19 compounds were identified that possessed IC50 values from 10 µM to 340 nM. The most potent inhibitor was MMV 1580488 (17), which was observed to have an IC50 of 340 nM. The selected hits serve as chemical leads that can be used for the development of potent inhibitors of the RpMetAp1 enzyme.


Assuntos
Rickettsia prowazekii , Rickettsia prowazekii/enzimologia , Metionil Aminopeptidases/antagonistas & inibidores , Relação Estrutura-Atividade , Estrutura Molecular , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Aminopeptidases/antagonistas & inibidores , Aminopeptidases/metabolismo , Relação Dose-Resposta a Droga
20.
Bioorg Med Chem Lett ; 108: 129799, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38754564

RESUMO

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.


Assuntos
Anemia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Macaca fascicularis , Inibidores de Prolil-Hidrolase , Animais , Anemia/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Administração Oral , Humanos , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/química , Inibidores de Prolil-Hidrolase/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Eritropoetina , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química
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