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Aminopyrazole based CDK9 PROTAC sensitizes pancreatic cancer cells to venetoclax.
King, Hannah M; Rana, Sandeep; Kubica, Sydney P; Mallareddy, Jayapal Reddy; Kizhake, Smitha; Ezell, Edward L; Zahid, Muhammad; Naldrett, Michael J; Alvarez, Sophie; Law, Henry C-H; Woods, Nicholas T; Natarajan, Amarnath.
Afiliação
  • King HM; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Rana S; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Kubica SP; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Mallareddy JR; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Kizhake S; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Ezell EL; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Zahid M; Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Naldrett MJ; Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska, Lincoln, NE 68588, USA.
  • Alvarez S; Proteomics & Metabolomics Facility, Nebraska Center for Biotechnology, University of Nebraska, Lincoln, NE 68588, USA.
  • Law HC; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Woods NT; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, USA.
  • Natarajan A; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68022, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68022, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, USA.
Bioorg Med Chem Lett ; 43: 128061, 2021 07 01.
Article em En | MEDLINE | ID: mdl-33895280
ABSTRACT
Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC50 = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Pirazóis / Quinase 9 Dependente de Ciclina / Inibidores de Proteínas Quinases Limite: Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Pirazóis / Quinase 9 Dependente de Ciclina / Inibidores de Proteínas Quinases Limite: Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos