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1.
J Med Chem ; 60(15): 6678-6692, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28671458

RESUMO

Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.


Assuntos
Aciltransferases/antagonistas & inibidores , Antineoplásicos/farmacologia , Maleimidas/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Piridazinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Inibidores do Citocromo P-450 CYP1A2/administração & dosagem , Inibidores do Citocromo P-450 CYP1A2/síntese química , Inibidores do Citocromo P-450 CYP1A2/farmacocinética , Inibidores do Citocromo P-450 CYP1A2/farmacologia , Inibidores do Citocromo P-450 CYP2D6/administração & dosagem , Inibidores do Citocromo P-450 CYP2D6/síntese química , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Maleimidas/administração & dosagem , Maleimidas/síntese química , Maleimidas/farmacocinética , Camundongos Endogâmicos BALB C , Camundongos Nus , Microssomos Hepáticos/metabolismo , Piridazinas/administração & dosagem , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Via de Sinalização Wnt , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Chem Inf Model ; 55(7): 1435-48, 2015 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-26024410

RESUMO

Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic xantine, a phtalimide, or a piperidine-maleimide scaffold.


Assuntos
Desenho de Fármacos , Proteínas de Membrana/antagonistas & inibidores , Modelos Moleculares , Proteínas Wnt/antagonistas & inibidores , Aciltransferases , Células HEK293 , Humanos , Conformação Molecular , Estereoisomerismo , Especificidade por Substrato
3.
J Med Chem ; 56(11): 4497-508, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23672613

RESUMO

Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.


Assuntos
Quinolinas/síntese química , Tanquirases/antagonistas & inibidores , Cristalografia por Raios X , Bases de Dados Factuais , Estabilidade de Medicamentos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Quinolinas/química , Solubilidade , Relação Estrutura-Atividade , Tanquirases/química , Termodinâmica
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