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Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.
He, Liqi; Zhang, Meng Yao; Cox, Matthew; Zhang, Qian; Donnell, Andrew F; Zhang, Yong; Tarby, Christine; Gill, Patrice; Subbaiah, Murugaiah A M; Ramar, Thangeswaran; Reddy, Maheswara; Puttapaka, Vijaya; Li, Yi-Xin; Sivaprakasam, Prasanna; Critton, David; Mulligan, Dawn; Xie, Chunshan; Ramakrishnan, Radha; Nagar, Jignesh; Dudhgaonkar, Shailesh; Murtaza, Anwar; Oderinde, Martins S; Schieven, Gary L; Mathur, Arvind; Gavai, Ashvinikumar V; Vite, Gregory; Gangwar, Sanjeev; Poudel, Yam B.
Afiliação
  • He L; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Zhang MY; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Cox M; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Zhang Q; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Donnell AF; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Zhang Y; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Tarby C; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Gill P; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Subbaiah MAM; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Ramar T; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Reddy M; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Puttapaka V; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Li YX; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Sivaprakasam P; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Critton D; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Mulligan D; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Xie C; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Ramakrishnan R; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Nagar J; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Dudhgaonkar S; Biocon Bristol Myers Squibb R&D Centre, Bangalore 560099, India.
  • Murtaza A; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Oderinde MS; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Schieven GL; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Mathur A; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Gavai AV; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Vite G; Research and Development, Bristol Myers Squibb, Princeton, New Jersey 08543, United States.
  • Gangwar S; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • Poudel YB; Research and Development, Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
ACS Med Chem Lett ; 15(2): 189-196, 2024 Feb 08.
Article em En | MEDLINE | ID: mdl-38352849
ABSTRACT
Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article