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Structure-Aided Development of Small-Molecule Inhibitors of ENPP1, the Extracellular Phosphodiesterase of the Immunotransmitter cGAMP.
Carozza, Jacqueline A; Brown, Jenifer A; Böhnert, Volker; Fernandez, Daniel; AlSaif, Yasmeen; Mardjuki, Rachel E; Smith, Mark; Li, Lingyin.
Afiliação
  • Carozza JA; Department of Chemistry, Stanford University, Stanford, CA 93405, USA; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA.
  • Brown JA; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA; Biophysics Program, Stanford University, Stanford, CA 93405, USA.
  • Böhnert V; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA; Department of Biochemistry, Stanford University, Stanford, CA 93405, USA.
  • Fernandez D; Stanford ChEM-H Macromolecular Structure Knowledge Center, Stanford University, Stanford, CA 93405, USA.
  • AlSaif Y; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA; Department of Biology, Stanford University, Stanford, CA 93405, USA.
  • Mardjuki RE; Department of Chemistry, Stanford University, Stanford, CA 93405, USA; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA.
  • Smith M; Stanford ChEM-H Medicinal Chemistry Knowledge Center, Stanford, CA 93405, USA.
  • Li L; Stanford ChEM-H, Stanford University, Stanford, CA 93405, USA; Department of Biochemistry, Stanford University, Stanford, CA 93405, USA. Electronic address: lingyinl@stanford.edu.
Cell Chem Biol ; 27(11): 1347-1358.e5, 2020 11 19.
Article em En | MEDLINE | ID: mdl-32726585
Cancer cells initiate an innate immune response by synthesizing and exporting the small-molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small-molecule ENPP1 inhibitors are much needed as tools to study the basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. In addition, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class inhibitors with Ki < 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirofosfatases / Inibidores Enzimáticos / Bibliotecas de Moléculas Pequenas / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirofosfatases / Inibidores Enzimáticos / Bibliotecas de Moléculas Pequenas / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article