7QHL
Crystal structure of Cyclin-dependent kinase 2/cyclin A in complex with 3,5,7-Substituted pyrazolo[4,3-d]pyrimidine inhibitor 24
Summary for 7QHL
| Entry DOI | 10.2210/pdb7qhl/pdb |
| Descriptor | Cyclin-dependent kinase 2, Cyclin-A2, 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine, ... (8 entities in total) |
| Functional Keywords | cyclin-dependent kinase, inhibitor, pyrazolo[4, 3-d]pyrimidine, cell cycle |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 129576.19 |
| Authors | Djukic, S.,Skerlova, J.,Rezacova, P. (deposition date: 2021-12-13, release date: 2022-07-06, Last modification date: 2024-11-06) |
| Primary citation | Jorda, R.,Havlicek, L.,Perina, M.,Vojackova, V.,Pospisil, T.,Djukic, S.,Skerlova, J.,Gruz, J.,Renesova, N.,Klener, P.,Rezacova, P.,Strnad, M.,Krystof, V. 3,5,7-Substituted Pyrazolo[4,3- d ]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders. J.Med.Chem., 65:8881-8896, 2022 Cited by PubMed Abstract: 3,5,7-Trisubstituted pyrazolo[4,3-]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)-pyrazolo[4,3-]pyrimidine () 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 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 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. PubMed: 35749742DOI: 10.1021/acs.jmedchem.1c02184 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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