Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
1.
Bioorg Med Chem Lett ; 29(16): 2316-2319, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31235263

RESUMO

The YAP-TEAD protein-protein interaction is a potential therapeutic target to treat cancers in which the Hippo signaling pathway is deregulated. However, the extremely large surface of interaction between the two proteins presents a formidable challenge for a small molecule interaction disrupter approach. We have accomplished progress towards showing the feasibility of this approach by the identification of a 15-mer peptide able to potently (nanomolar range) disrupt the YAP-TEAD interaction by targeting only one of the two important sites of interaction. This peptide, incorporating non-natural amino acids selected by structure-based design, is derived from the Ω-loop sequence 85-99 of YAP.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Desenho de Fármacos , Peptídeos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Fatores de Transcrição/química , Proteínas de Sinalização YAP
2.
Bioorg Med Chem Lett ; 28(20): 3404-3408, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217415

RESUMO

Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.


Assuntos
Antineoplásicos/farmacologia , Multimerização Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirazóis/farmacologia , Pirrolidinonas/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cães , Haplorrinos , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacocinética , Pirrolidinonas/síntese química , Pirrolidinonas/química , Pirrolidinonas/farmacocinética , Ratos Sprague-Dawley , Estereoisomerismo
3.
Bioorg Med Chem Lett ; 26(19): 4837-4841, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27542305

RESUMO

The p53-MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein-protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53-MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53-MDM2 inhibitor that recently entered phase I clinical trial.


Assuntos
Descoberta de Drogas , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores , Cristalografia por Raios X , Transferência Ressonante de Energia de Fluorescência , Conformação Molecular , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo
4.
Bioorg Med Chem Lett ; 25(17): 3621-5, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26141769

RESUMO

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.


Assuntos
Isoquinolinas/química , Isoquinolinas/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/antagonistas & inibidores
5.
Bioorg Med Chem Lett ; 24(9): 2110-4, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24704029

RESUMO

Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53-MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein-protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
6.
Protein Sci ; 32(1): e4545, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36522189

RESUMO

The yes-associated protein (YAP) regulates the transcriptional activity of the TEAD transcription factors that are key in the control of organ morphogenesis. YAP interacts with TEAD via three secondary structure elements: a ß-strand, an α-helix, and an Ω-loop. Earlier results have shown that the ß-strand has only a marginal contribution in the YAP:TEAD interaction, but we show here that it significantly enhances the affinity of YAP for the Drosophila homolog of TEAD, scalloped (Sd). Nuclear magnetic resonance shows that the ß-strand adopts a more rigid conformation once bound to Sd; pre-steady state kinetic measurements show that the YAP:Sd complex is more stable. Although the crystal structures of the YAP:TEAD and YAP:Sd complexes reveal no differences at the binding interface that could explain these results. Molecular Dynamics simulations are in line with our experimental findings regarding ß-strand stability and overall binding affinity of YAP to TEAD and Sd. In particular, RMSF, correlated motion and MMGBSA analyses suggest that ß-sheet fluctuations play a relevant role in YAP53-57 ß-strand dissociation from TEAD4 and contribute to the lower affinity of YAP for TEAD4. Identifying a clear mechanism leading to the difference in YAP's ß-strand stability proved to be challenging, pointing to the potential relevance of multiple modest structural changes or fluctuations for regulation of binding affinity.


Assuntos
Fatores de Transcrição de Domínio TEA , Fatores de Transcrição , Fatores de Transcrição/química , Proteínas de Ligação a DNA/química , Conformação Proteica em Folha beta , Regulação da Expressão Gênica , Ligação Proteica
7.
ACS Chem Biol ; 18(3): 643-651, 2023 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-36825662

RESUMO

The TEAD transcription factors are the most distal elements of the Hippo pathway, and their transcriptional activity is regulated by several proteins, including YAP. In some cancers, the Hippo pathway is deregulated and inhibitors of the YAP:TEAD interaction are foreseen as new anticancer drugs. The binding of YAP to TEAD is driven by the interaction of an α-helix and an Ω-loop present in its TEAD-binding domain with two distinct pockets at the TEAD surface. Using the mRNA-based display technique to screen a library of in vitro-translated cyclic peptides, we identified a peptide that binds with a nanomolar affinity to TEAD. The X-ray structure of this peptide in complex with TEAD reveals that it interacts with the α-helix pocket. Under our experimental conditions, this peptide can form a ternary complex with TEAD and YAP. Furthermore, combining it with a peptide binding to the Ω-loop pocket gives an additive inhibitory effect on the YAP:TEAD interaction. Overall, our results show that it is possible to identify nanomolar inhibitors of the YAP:TEAD interaction that bind to the α-helix pocket, suggesting that developing such compounds might be a strategy to treat cancers where the Hippo pathway is deregulated.


Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Conformação Proteica em alfa-Hélice , Fatores de Transcrição de Domínio TEA , Peptídeos/química
8.
ChemMedChem ; 18(11): e202300051, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36988034

RESUMO

The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Ω-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time.


Assuntos
Neoplasias , Fatores de Transcrição , Animais , Camundongos , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
9.
Bioorg Med Chem Lett ; 22(10): 3498-502, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22507962

RESUMO

Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.


Assuntos
Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Valina/metabolismo , Modelos Moleculares , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
11.
ChemMedChem ; 17(19): e202200303, 2022 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-35950546

RESUMO

Inhibition of the YAP-TEAD protein-protein interaction is an attractive therapeutic concept under intense investigation with the objective to treat cancers associated with a dysregulation of the Hippo pathway. However, owing to the very extended surface of interaction of the two proteins, the identification of small drug-like molecules able to efficiently prevent YAP from binding to TEAD by direct competition has been elusive so far. We disclose here the discovery of the first class of small molecules potently inhibiting the YAP-TEAD interaction by binding at one of the main interaction sites of YAP at the surface of TEAD. These inhibitors, providing a path forward to pharmacological intervention in the Hippo pathway, evolved from a weakly active virtual screening hit advanced to high potency by structure-based design.


Assuntos
Neoplasias , Fatores de Transcrição , Proteínas Adaptadoras de Transdução de Sinal/química , Humanos , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP
12.
Bioorg Med Chem Lett ; 21(11): 3358-61, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21531559

RESUMO

Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models.


Assuntos
Quinazolinonas/síntese química , Receptores de AMPA/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Ligação Competitiva/efeitos dos fármacos , Cristalografia por Raios X , Camundongos , Estrutura Molecular , Quinazolinonas/química , Quinazolinonas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
13.
RSC Chem Biol ; 2(6): 1661-1668, 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34977581

RESUMO

Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in vitro-translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

14.
Nat Commun ; 12(1): 898, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563973

RESUMO

Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.


Assuntos
Tolerância a Radiação , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cell Chem Biol ; 28(9): 1271-1282.e12, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-33894161

RESUMO

Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Proteínas Morfogenéticas Ósseas/metabolismo , Tacrolimo/farmacologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fenótipo , Tacrolimo/análogos & derivados , Tacrolimo/química
16.
FEBS J ; 286(12): 2381-2398, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30903741

RESUMO

Four TEAD transcription factors (TEAD1-4) mediate the signalling output of the Hippo pathway that controls organ size in humans. TEAD transcriptional activity is regulated via interactions with the YAP, TAZ and VGLL proteins. A mutation in the TEAD1 gene, Tyr421His, has been identified in patients suffering from Sveinsson's chorioretinal atrophy (SCA), an autosomal dominant eye disease. This mutation prevents the YAP/TAZ:TEAD1 interaction. In this study, we measure the affinity of YAP, TAZ and VGLL1 for the four human TEADs and find that they have a similar affinity for all TEADs. We quantitate the effect of the mutation found in SCA patients and show that it destabilizes the YAP/TAZ:TEAD interaction by about 3 kcal·mol-1 . We determine the structure of YAP in complex with this mutant form of TEAD and show that the histidine residue adopts different conformations at the binding interface. The presence of this flexible residue induces the destabilization of several H-bonds and the loss of van der Waals contacts, which explains why the Tyr421HisTEAD1 mutation has such a large destabilizing effect on the formation of the YAP:TEAD complex. DATABASE: The crystallographic data have been deposited at the RSCB Protein Data Bank (PDB, www.pdb.org) with the access codes: 6HIL (wtYAP :Tyr421HisTEAD1 ), 6HIK (wtYAP :Tyr429HisTEAD4 ).


Assuntos
Proteínas de Ciclo Celular/genética , Distrofias Hereditárias da Córnea/genética , Proteínas de Ligação a DNA/química , Proteínas Nucleares/química , Mapas de Interação de Proteínas/genética , Degeneração Retiniana/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Aciltransferases , Proteínas de Ciclo Celular/química , Distrofias Hereditárias da Córnea/patologia , Cristalografia por Raios X , Proteínas de Ligação a DNA/genética , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Mutação/genética , Proteínas Nucleares/genética , Ligação Proteica/genética , Degeneração Retiniana/patologia , Transdução de Sinais/genética , Fatores de Transcrição de Domínio TEA
17.
ChemMedChem ; 14(14): 1305-1314, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31066983

RESUMO

Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin-dependent p53 protein degradation. Activation of p53 by inhibitors of the p53-Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X-ray structures for Hdm2 and five new X-ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18-crown-ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X-ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP-CGM097 and NVP-HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Compostos Heterocíclicos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/química , Cristalografia por Raios X , Compostos Heterocíclicos/química , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas c-mdm2/química
18.
J Med Chem ; 62(23): 10816-10832, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31729873

RESUMO

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.


Assuntos
Hipersensibilidade Tardia/tratamento farmacológico , Imidazóis/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Administração Oral , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Transferência Ressonante de Energia de Fluorescência , Meia-Vida , Imidazóis/química , Imidazóis/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos
19.
Protein Sci ; 27(10): 1810-1820, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30058229

RESUMO

Many interactions between proteins are mediated by intrinsically disordered regions (IDRs). Intrinsically disordered proteins (IDPs) do not adopt a stable three-dimensional structure in their unbound form, but they become more structured upon binding to their partners. In this communication, we study how a bound IDR adapts to mutations, preventing the formation of hydrogen bonds at the binding interface that needs a precise positioning of the interacting residues to be formed. We use as a model the YAP:TEAD interface, where one YAP (IDP) and two TEAD residues form hydrogen bonds via their side chain. Our study shows that the conformational flexibility of bound YAP and the reorganization of water molecules at the interface help to reduce the energetic constraints created by the loss of H-bonds at the interface. The residual flexibility/dynamic of bound IDRs and water might, therefore, be a key for the adaptation of IDPs to different interface landscapes and to mutations occurring at binding interfaces.


Assuntos
Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Mutação , Ligação Proteica , Conformação Proteica , Termodinâmica , Água/química
20.
J Med Chem ; 61(15): 6724-6735, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-29990434

RESUMO

The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats.


Assuntos
Descoberta de Drogas , Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Animais , Domínio Catalítico , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Modelos Moleculares , Ratos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA