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1.
Cell Chem Biol ; 28(12): 1750-1757.e5, 2021 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33725479

RESUMO

Signaling pathways are frequently activated through signal-receiving membrane proteins, and the discovery of small molecules targeting these receptors may yield insights into their biology. However, due to their intrinsic properties, membrane protein targets often cannot be identified by means of established approaches, in particular affinity-based proteomics, calling for the exploration of new methods. Here, we report the identification of indophagolin as representative member of an indoline-based class of autophagy inhibitors through a target-agnostic phenotypic assay. Thermal proteome profiling and subsequent biochemical validation identified the purinergic receptor P2X4 as a target of indophagolin, and subsequent investigations suggest that indophagolin targets further purinergic receptors. These results demonstrate that thermal proteome profiling may enable the de novo identification of membrane-bound receptors as cellular targets of bioactive small molecules.


Assuntos
Autofagia/efeitos dos fármacos , Proteoma/genética , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/metabolismo , Temperatura , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X4/genética , Relação Estrutura-Atividade , Células Tumorais Cultivadas
2.
Angew Chem Int Ed Engl ; 58(47): 17016-17025, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31469221

RESUMO

Bioactive compound design based on natural product (NP) structure may be limited because of partial coverage of NP-like chemical space and biological target space. These limitations can be overcome by combining NP-centered strategies with fragment-based compound design through combination of NP-derived fragments to afford structurally unprecedented "pseudo-natural products" (pseudo-NPs). The design, synthesis, and biological evaluation of a collection of indomorphan pseudo-NPs that combine biosynthetically unrelated indole- and morphan-alkaloid fragments are described. Indomorphane derivative Glupin was identified as a potent inhibitor of glucose uptake by selectively targeting and upregulating glucose transporters GLUT-1 and GLUT-3. Glupin suppresses glycolysis, reduces the levels of glucose-derived metabolites, and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUT-1 and GLUT-3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity.


Assuntos
Produtos Biológicos/farmacologia , Proliferação de Células , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 3/antagonistas & inibidores , Glucose/metabolismo , Morfinanos/síntese química , Neoplasias/tratamento farmacológico , Transporte Biológico , Ciclo Celular , Glicólise , Humanos , Células Tumorais Cultivadas
3.
Angew Chem Int Ed Engl ; 56(28): 8153-8157, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28544137

RESUMO

Autophagy is a critical regulator of cellular homeostasis and metabolism. Interference with this process is considered a new approach for the treatment of disease, in particular cancer and neurological disorders. Therefore, novel small-molecule autophagy modulators are in high demand. We describe the discovery of autophinib, a potent autophagy inhibitor with a novel chemotype. Autophinib was identified by means of a phenotypic assay monitoring the formation of autophagy-induced puncta, indicating accumulation of the lipidated cytosolic protein LC3 on the autophagosomal membrane. Target identification and validation revealed that autophinib inhibits autophagy induced by starvation or rapamycin by targeting the lipid kinase VPS34.


Assuntos
Autofagia/efeitos dos fármacos , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Autofagossomos/efeitos dos fármacos , Descoberta de Drogas , Células HEK293 , Células HeLa , Humanos , Células MCF-7 , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Sirolimo/farmacologia , Relação Estrutura-Atividade
4.
Org Biomol Chem ; 14(25): 5922-7, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27245438

RESUMO

A series of cyclopenta[c]pyridine aldosterone synthase (AS) inhibitors were conveniently accessed using batch or continuous flow Kondrat'eva reactions. Preparation of the analogous cyclohexa[c]pyridines led to the identification of a potent and more selective AS inhibitor. The structure-activity-relationship (SAR) in this new series was rationalized using binding mode models in the crystal structure of AS.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Técnicas de Química Sintética , Citocromo P-450 CYP11B2/química , Inibidores das Enzimas do Citocromo P-450/química , Humanos , Modelos Moleculares , Conformação Proteica , Piridinas/química , Relação Estrutura-Atividade
5.
Chemistry ; 21(23): 8455-63, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25944543

RESUMO

A Rebek imide receptor with an acetylene-linked phenyl ring complexes 2,6-di(isobutyramido)pyridine in (CDCl2 )2 via triple H-bonding and π-π-stacking interactions, and the influence of para-substituents on both rings was investigated by (1) H NMR binding titrations. When the phenyl ring was extended to biphenyl and the C(4)-pyridine substituent varied, interaction energies increased in the order CH3 CH2 ⋅⋅⋅phenyl

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