RESUMO
Targeted covalent inhibition of disease-associated proteins has become a powerful methodology in the field of drug discovery, leading to the approval of new therapeutics. Nevertheless, current approaches are often limited owing to their reliance on a cysteine residue to generate the covalent linkage. Here we used aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain, and generated to our knowledge the first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies. These covalent binders exhibited improved potency in comparison to noncovalent congeners, as demonstrated in biochemical and cell-based assays. We identified Lys234 as the residue involved in covalent modification, via point mutation. The covalent binders discovered in this study will serve as useful starting points for the development of Mcl-1 therapeutics and probes to interrogate Mcl-1-dependent biological phenomena.
Assuntos
Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Lisina/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Ácidos Borônicos/síntese química , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Lisina/metabolismo , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Relação Estrutura-AtividadeRESUMO
We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors.
Assuntos
Imidazóis/farmacologia , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/síntese química , Imidazóis/química , Janus Quinase 1/metabolismo , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-AtividadeRESUMO
The discovery and optimization of a series of 6-aryl-azabenzimidazole inhibitors of TBK1 and IKK-ε is described. Various internal azabenzimidazole leads and reported TBK1/IKK-ε inhibitors were docked into a TBK1 homology model. The resulting overlays inspired a focused screen of 6-substituted azabenzimidazoles against TBK1/IKK-ε. This screen resulted in initial hit compound 3. The TBK1/IKK-ε enzyme and cell potency of this compound was further improved using structure guided drug design. Systematic exploration of the C6 aryl group led to compound 19, a potent inhibitor of TBK1 with selectivity against cell cycle kinases CDK2 and Aurora B. Further elaboration and optimization gave compound 25, a single digit nM inhibitor of TBK1. These compounds may serve as in vitro probes to evaluate TBK1/IKK-ε as an oncology target.
Assuntos
Benzimidazóis/farmacologia , Descoberta de Drogas , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Humanos , Quinase I-kappa B/metabolismo , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aurora Quinase B , Aurora Quinases , Compostos Aza/química , Compostos Aza/farmacologia , Quinase 2 Dependente de Ciclina/metabolismo , Desenho de Fármacos , Células HEK293 , Humanos , Quinase I-kappa B/metabolismo , Modelos Moleculares , Neoplasias/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
Assuntos
Neoplasias da Mama , Ciclo Celular , Quinases Ciclina-Dependentes , Descoberta de Drogas , Inibidores de Proteínas Quinases , Animais , Feminino , Humanos , Camundongos , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Quinase Ativadora de Quinase Dependente de Ciclina , Quinases Ciclina-Dependentes/antagonistas & inibidores , Camundongos Endogâmicos BALB C , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As an anti-inflammatory strategy, MAPK-activated protein kinase-2 (MK2) inhibition can potentially avoid the clinical failures seen for direct p38 inhibitors, especially tachyphylaxis. CC-99677, a selective targeted covalent MK2 inhibitor, employs a rare chloropyrimidine that bonds to the sulfur of cysteine 140 in the ATP binding site via a nucleophilic aromatic substitutions (SNAr) mechanism. This irreversible mechanism translates biochemical potency to cells shown by potent inhibition of heat shock protein 27 (HSP27) phosphorylation in LPS-activated monocytic THP-1 cells. The cytokine inhibitory profile of CC-99677 differentiates it from known p38 inhibitors, potentially suppressing a p38 pathway inflammatory response while avoiding tachyphylaxis. Dosed orally, CC-99677 is efficacious in a rat model of ankylosing spondylitis. Single doses, 3 to 400 mg, in healthy human volunteers show linear pharmacokinetics and apparent sustained tumor necrosis factor-α inhibition, with a favorable safety profile. These results support further development of CC-99677 for autoimmune diseases like ankylosing spondylitis.
Assuntos
Doenças Autoimunes , Espondilite Anquilosante , Trifosfato de Adenosina , Animais , Anti-Inflamatórios , Doenças Autoimunes/tratamento farmacológico , Cisteína , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos , Proteínas Serina-Treonina Quinases , Ratos , Enxofre , Fator de Necrose Tumoral alfa , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Interruption of TGFbeta signaling through inhibition of the TGFbetaR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFbetaR1 kinase inhibitors containing a pyrazolone core. Most TGFbetaR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazolonas/química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazolonas/síntese química , Pirazolonas/farmacocinética , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Relação Estrutura-AtividadeRESUMO
JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.
Assuntos
Indóis/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Indóis/síntese química , Indóis/farmacocinética , Camundongos Nus , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: TGF-beta plays a significant role in vascular injury-induced stenosis. This study evaluates the efficacy of a novel, small molecule inhibitor of ALK5/ALK4 kinase, in the rat carotid injury model of vascular fibrosis. METHODS AND RESULTS: The small molecule, SM16, was shown to bind with high affinity to ALK5 kinase ATP binding site using a competitive binding assay and biacore analysis. SM16 blocked TGF-beta and activin-induced Smad2/3 phosphorylation and TGF-beta-induced plasminogen activator inhibitor (PAI)-luciferase activity in cells. Good overall selectivity was demonstrated in a large panel of kinase assays, but SM16 also showed nanomolar inhibition of ALK4 and weak (micromolar) inhibition of Raf and p38. In the rat carotid injury model, SM16 dosed once daily orally at 15 or 30 mg/kg SM16 for 14 days caused significant inhibition of neointimal thickening and lumenal narrowing. SM16 also prevented induction of adventitial smooth muscle alpha-actin-positive myofibroblasts and the production of intimal collagen, but did not decrease the percentage of proliferative cells. CONCLUSIONS: These results are the first to demonstrate the efficacy of an orally active, small-molecule ALK5/ALK4 inhibitor in a vascular fibrosis model and suggest the potential therapeutic application of these inhibitors in vascular fibrosis.
Assuntos
Compostos Azabicíclicos/farmacologia , Lesões das Artérias Carótidas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Ativinas Tipo I/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Compostos Azabicíclicos/administração & dosagem , Compostos Azabicíclicos/metabolismo , Sítios de Ligação , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Linhagem Celular , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Humanos , Masculino , Mioblastos de Músculo Liso/efeitos dos fármacos , Mioblastos de Músculo Liso/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor do Fator de Crescimento Transformador beta Tipo I , Fator de Crescimento Transformador beta/fisiologiaRESUMO
The 4-(5-fluoro-6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-1H-imidazol-2-ylamine 3 is a potent and selective inhibitor of TGF-betaR1. Substitution of the amino group of 3 typically led to a slight decrease in the affinity for the receptor and in TGF-beta-inducted PAI-luciferase reporter activity. However, 2-acetamidoimidazoles were identified as attractive candidates for further optimization as a result of their significant activity combined to their superior pharmacokinetic profile.
Assuntos
Química Farmacêutica/métodos , Imidazóis/síntese química , Imidazóis/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Luciferases/metabolismo , Masculino , Modelos Biológicos , Conformação Molecular , Ratos , Ratos Sprague-DawleyRESUMO
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and have thus been implicated in both cancer and inflammatory diseases. The JAK family consists of four highly homologous members: JAK1-3 and TYK2. The development of small-molecule inhibitors that are selective for a specific family member would represent highly desirable tools for deconvoluting the intricacies of JAK family biology. Herein, we report the discovery of a potent JAK1 inhibitor, 24, which displays â¼1000-fold selectivity over the other highly homologous JAK family members (determined by biochemical assays), while also possessing good selectivity over other kinases (determined by panel screening). Moreover, this compound was demonstrated to be orally bioavailable and possesses acceptable pharmacokinetic parameters. In an in vivo study, the compound was observed to dose dependently modulate the phosphorylation of STAT3 (a downstream marker of JAK1 inhibition).
Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Humanos , Janus Quinase 1/química , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Janus Quinase 3/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.
Assuntos
Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-bcl-6/antagonistas & inibidoresRESUMO
Here we present a new strategy for designing and filtering potentially massive combinatorial libraries using structural information of a binding site. We have developed a variation of the structural interaction fingerprint (SIFt) named r-SIFt, which incorporates the binding interactions of variable fragments in a combinatorial library. This method takes into account the 3D structure of the active site of the target molecule and translates desirable ligand-target binding interactions into library filtering constraints. We show using the MAP kinase p38 as a test case that we can efficiently analyze and classify compounds on the basis of their abilities to interact with the target in the desired binding mode. On the basis of these classifications, decision tree models were generated using the molecular descriptors of the compounds as predictor variables. Our results suggest that r-SIFt coupled with the classification models should be a valuable tool for structure-based focusing of combinatorial chemical libraries.
Assuntos
Técnicas de Química Combinatória , Bases de Dados Factuais , Bases de Conhecimento , Ligantes , Proteínas/química , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Modelos Moleculares , Estrutura Molecular , Ligação ProteicaRESUMO
A subset of the compound repository for lead identification at Biogen Idec was characterized for its chemical stability over a 3-year period. Compounds were stored at 4 degrees C as 10 mM DMSO stocks, and a small subset of compounds was stored as lyophilized dry films. Compound integrity of 470 discrete compounds (Compound Set I) and 1917 combinatorial chemistry-derived compounds (Compound Set II) was evaluated by liquid chromatography/mass spectrometry from the time of acquisition into the library collection and after 3 years of storage. Loss of compound integrity over the 3 years of storage was observed across the 2 subsets tested. Of Compound Set I, 63% of samples retained > 80% purity, whereas 57% of samples from Compound Set II had purity greater than 60%. The stability of the lyophilized samples was superior to the samples stored as DMSO solution. Although storage at 4 degrees C as DMSO solution was adequate for the majority of compounds, the authors observed and quantified the level of degradation within the compound collection. Their study provides general insight into compound storage and selection of library subsets for future lead identification activities.
Assuntos
Técnicas de Química Combinatória/métodos , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/normas , Cromatografia Líquida , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Espectrometria de Massas , Preparações Farmacêuticas/química , Controle de Qualidade , Fatores de TempoRESUMO
The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development and adult tissue regeneration. Impaired Wnt pathway regulation, arising from mutations in Wnt signaling components, such as Axin, APC, and ß-catenin, results in uncontrolled cell growth and triggers oncogenesis. To explore the reported link between CK2 kinase activity and Wnt pathway signaling, we sought to identify a potent, selective inhibitor of CK2 suitable for proof of concept studies in vivo. Starting from a pyrazolo[1,5-a]pyrimidine lead (2), we identified compound 7h, a potent CK2 inhibitor with picomolar affinity that is highly selectivity against other kinase family enzymes and inhibits Wnt pathway signaling (IC50 = 50 nM) in DLD-1 cells. In addition, compound 7h has physicochemical properties that are suitable for formulation as an intravenous solution, has demonstrated good pharmacokinetics in preclinical species, and exhibits a high level of activity as a monotherapy in HCT-116 and SW-620 xenografts.
RESUMO
A novel series of covalent inhibitors of EGFR (epidermal growth factor receptor) kinase was discovered through a combination of subset screening and structure-based design. These compounds preferentially inhibit mutant forms of EGFR (activating mutant and T790M mutant) over wild-type EGFR in cellular assays measuring EGFR autophosphorylation and proliferation, suggesting an improved therapeutic index in non-small cell lung cancer patients would be achievable relative to established EGFR inhibitors. We describe our design approaches, resulting in the identification of the lead compound 5, and our efforts to develop an understanding of the structure-activity relationships within this series. In addition, strategies to overcome challenges around metabolic stability and aqueous solubility are discussed. Despite limitations in its physical properties, 5 is orally bioavailable in mice and demonstrates pronounced antitumor activity in in vivo models of mutant EGFR-driven cancers.
RESUMO
Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.
RESUMO
A major challenge facing structure-based drug discovery efforts is how to leverage the massive amount of experimental (X-ray and NMR) and virtual structural information generated from drug discovery projects. Many important drug targets have large numbers of protein-inhibitor complexes, necessitating tools to compare and contrast their similarities and differences. This information would be valuable for understanding potency and selectivity of inhibitors and could be used to define target constraints to assist virtual screening. We describe a profile-based approach that enables us to capture the conservation of interactions between a set of protein-ligand receptor complexes. The use of profiles provides a sensitive means to compare multiple inhibitors binding to a drug target. We demonstrate the utility of profile-based analysis of small molecule complexes from the protein-kinase family to identify similarities and differences in binding of ATP, p38, and CDK2 compounds to kinases and how these profiles can be applied to differentiate the selectivity of these inhibitors. Importantly, our virtual screening results demonstrate superior enrichment of kinase inhibitors using profile-based methods relative to traditional scoring functions. Interaction-based analysis should provide a valuable tool for understanding inhibitor binding to other important drug targets.
Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Algoritmos , Quinases relacionadas a CDC2 e CDC28/química , Quinases relacionadas a CDC2 e CDC28/metabolismo , Quinase 2 Dependente de Ciclina , Bases de Dados Factuais , Bases de Dados de Proteínas , Modelos Moleculares , Modelos Teóricos , Inibidores de Proteínas Quinases/química , Proteínas Quinases/química , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Representing and understanding the three-dimensional (3D) structural information of protein-ligand complexes is a critical step in the rational drug discovery process. Traditional analysis methods are proving inadequate and inefficient in dealing with the massive amount of structural information being generated from X-ray crystallography, NMR, and in silico approaches such as structure-based docking experiments. Here, we present SIFt (structural interaction fingerprint), a novel method for representing and analyzing 3D protein-ligand binding interactions. Key to this approach is the generation of an interaction fingerprint that translates 3D structural binding information from a protein-ligand complex into a one-dimensional binary string. Each fingerprint represents the "structural interaction profile" of the complex that can be used to organize, analyze, and visualize the rich amount of information encoded in ligand-receptor complexes and also to assist database mining. We have applied SIFt to tackle three common tasks in structure-based drug design. The first involved the analysis and organization of a typical set of results generated from a docking study. Using SIFt, docking poses with similar binding modes were identified, clustered, and subsequently compared with conventional scoring function information. A second application of SIFt was to analyze approximately 90 known X-ray crystal structures of protein kinase-inhibitor complexes obtained from the Protein Databank. Using SIFt, we were able to organize the structures and reveal striking similarities and diversity between their small molecule binding interactions. Finally, we have shown how SIFt can be used as an effective molecular filter during the virtual chemical library screening process to select molecules with desirable binding mode(s) and/or desirable interaction patterns with the protein target. In summary, SIFt shows promise to fully leverage the wealth of information being generated in rational drug design.
Assuntos
Inibidores Enzimáticos/química , Proteínas Quinases/química , Sítios de Ligação , Cristalografia por Raios X , Bases de Dados Factuais , Ligantes , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases , Relação Quantitativa Estrutura-AtividadeRESUMO
Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.