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Discovery of a new series of PI3K-δ inhibitors from Virtual Screening.
Fradera, Xavier; Deng, Qiaolin; Achab, Abdelganhi; Garcia, Yudith; Kattar, Solomon D; McGowan, Meredeth A; Methot, Joey L; Wilson, Kevin; Zhou, Hua; Shaffer, Lynsey; Goldenblatt, Peter; Tong, Vincent; Augustin, Martin A; Altman, Michael D; Lesburg, Charles A; Shah, Sanjiv; Katz, Jason D.
  • Fradera X; Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA. Electronic address: xavier.fradera@merck.com.
  • Deng Q; Computational and Structural Chemistry, Merck & Co., Inc., Kenilworth, NJ, USA.
  • Achab A; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Garcia Y; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Kattar SD; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • McGowan MA; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Methot JL; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Wilson K; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Zhou H; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Shaffer L; Quantitative Biosciences, Merck & Co., Inc., Boston, MA, USA.
  • Goldenblatt P; Quantitative Biosciences, Merck & Co., Inc., Boston, MA, USA.
  • Tong V; PPDM, Merck & Co., Inc., Boston, MA, USA.
  • Augustin MA; Proteros Biostructures GmbH, Martinsried, Germany.
  • Altman MD; Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Lesburg CA; Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA, USA.
  • Shah S; Quantitative Biosciences, Merck & Co., Inc., Boston, MA, USA.
  • Katz JD; Discovery Chemistry, Merck & Co., Inc., Boston, MA, USA.
Bioorg Med Chem Lett ; 42: 128046, 2021 06 15.
Article en En | MEDLINE | ID: mdl-33865969
ABSTRACT
PI3K-δ mediates key immune cell signaling pathways and is a target of interest for treatment of oncological and immunological disorders. Here we describe the discovery and optimization of a novel series of PI3K-δ selective inhibitors. We first identified hits containing an isoindolinone scaffold using a combined ligand- and receptor-based virtual screening workflow, and then improved potency and selectivity guided by structural data and modeling. Careful optimization of molecular properties led to compounds with improved permeability and pharmacokinetic profile, and high potency in a whole blood assay.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ftalimidas / Descubrimiento de Drogas / Fosfatidilinositol 3-Quinasa Clase I / Inhibidores de las Quinasa Fosfoinosítidos-3 Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Ftalimidas / Descubrimiento de Drogas / Fosfatidilinositol 3-Quinasa Clase I / Inhibidores de las Quinasa Fosfoinosítidos-3 Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Año: 2021 Tipo del documento: Article