Your browser doesn't support javascript.
loading
3,5,7-Substituted Pyrazolo[4,3-d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders.
Jorda, Radek; Havlícek, Libor; Perina, Miroslav; Vojácková, Veronika; Pospísil, Tomás; Djukic, Stefan; Skerlová, Jana; Grúz, Jirí; Renesová, Nicol; Klener, Pavel; Rezácová, Pavlína; Strnad, Miroslav; Krystof, Vladimír.
Afiliación
  • Jorda R; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Havlícek L; Isotope Laboratory, Institute of Experimental Botany, Czech Academy of Sciences, Vídenská 1083, 14220 Prague, Czech Republic.
  • Perina M; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Vojácková V; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Pospísil T; Department of Chemical Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Djukic S; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Nám. 2, 16610 Prague, Czech Republic.
  • Skerlová J; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Nám. 2, 16610 Prague, Czech Republic.
  • Grúz J; Institute of Molecular Genetics, Czech Academy of Sciences, Vídenská 1083, 14220 Prague, Czech Republic.
  • Renesová N; Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Slechtitelu 27, 78371 Olomouc, Czech Republic.
  • Klener P; First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic.
  • Rezácová P; First Faculty of Medicine, Institute of Pathological Physiology, Charles University, 12108 Prague, Czech Republic.
  • Strnad M; First Department of Internal Medicine-Hematology, General University Hospital and First Faculty of Medicine, Charles University, 12808 Prague, Czech Republic.
  • Krystof V; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Nám. 2, 16610 Prague, Czech Republic.
J Med Chem ; 65(13): 8881-8896, 2022 07 14.
Article en En | MEDLINE | ID: mdl-35749742
3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinasas Ciclina-Dependientes / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: República Checa Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Quinasas Ciclina-Dependientes / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: República Checa Pais de publicación: Estados Unidos