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J Med Chem ; 62(16): 7400-7416, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31246024


In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

J Chem Inf Model ; 57(8): 1881-1894, 2017 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28727915


A novel method for exploring macrocycle conformational space, Prime macrocycle conformational sampling (Prime-MCS), is introduced and evaluated in the context of other available algorithms (Molecular Dynamics, LowModeMD in MOE, and MacroModel Baseline Search). The algorithms were benchmarked on a data set of 208 macrocycles which was curated for diversity from the Cambridge Structural Database, the Protein Data Bank, and the Biologically Interesting Molecule Reference Dictionary. The algorithms were evaluated in terms of accuracy (ability to reproduce the crystal structure), diversity (coverage of conformational space), and computational speed. Prime-MCS most reliably reproduced crystallographic structures for RMSD thresholds >1.0 Å, most often produced the most diverse conformational ensemble, and was most often the fastest algorithm. Detailed analysis and examination of both typical and outlier cases were performed to reveal characteristics, shortcomings, expected performance, and complementarity of the methods.

Compostos Macrocíclicos/química , Simulação de Dinâmica Molecular , Conformação Molecular , Termodinâmica , Fatores de Tempo
ACS Med Chem Lett ; 6(7): 770-5, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26191364


A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.

J Med Chem ; 58(6): 2855-61, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25695766


Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.

Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Compostos Macrocíclicos/química , Compostos Macrocíclicos/uso terapêutico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Cristalografia por Raios X , Descoberta de Drogas , Feminino , Biblioteca Gênica , Humanos , Compostos Macrocíclicos/farmacocinética , Camundongos , Modelos Moleculares , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
J Chem Inf Model ; 53(7): 1576-88, 2013 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-23809058


We describe an extension to the matched molecular pairs approach that merges pairwise activity differences with three-dimensional contextual information derived from X-ray crystal structures and binding pose predictions. The incorporation of 3D binding poses allows the direct comparison of structural changes to diverse chemotypes in particular binding pockets, facilitating the transfer of SAR from one series to another. Integrating matched pair data with the receptor structure can also highlight activity patterns within the binding site--for example, "hot spot" regions can be visualized where changes in the ligand structure are more likely to impact activity. The method is illustrated using P38α structural and activity data to generate novel hybrid ligands, identify SAR transfer networks, and annotate the receptor binding site.

Desenho de Drogas , Proteína Quinase 14 Ativada por Mitógeno/química , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Anotação de Sequência Molecular , Sítios de Ligação , Bases de Dados de Produtos Farmacêuticos , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Relação Estrutura-Atividade
J Med Chem ; 54(1): 54-66, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21128601


A kinome-wide selectivity screen of >20000 compounds with a rich representation of many structural classes has been completed. Analysis of the selectivity patterns for each class shows that a broad spectrum of structural scaffolds can achieve specificity for many kinase families. Kinase selectivity and potency are inversely correlated, a trend that is also found in a large set of kinase functional data. Although selective and nonselective compounds are mostly similar in their physicochemical characteristics, we identify specific features that are present more frequently in compounds that bind to many kinases. Our results support a scaffold-oriented approach for building compound collections to screen kinase targets.

Fosfotransferases/antagonistas & inibidores , Fosfotransferases/química , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Bibliotecas de Moléculas Pequenas , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Ensaios de Triagem em Larga Escala , Ligação Proteica , Homologia de Sequência de Aminoácidos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/química