2. Academic Validation
  3. CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609

CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609

  • Int J Biol Macromol. 2025 Mar:294:139117. doi: 10.1016/j.ijbiomac.2024.139117.
Jana Škerlová 1,  Veronika Krejčiříková 2,  Miroslav Peřina 3,  Veronika Vojáčková 3,  Milan Fábry 2,  Vladimír Kryštof 4,  Radek Jorda 5,  Pavlína Řezáčová 2
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic. Electronic address: jana.skerlova@uochb.cas.cz.
  • 2 Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.
  • 3 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Olomouc, Czech Republic.
  • 4 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech Republic.
  • 5 Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Olomouc, Czech Republic. Electronic address: radek.jorda@upol.cz.
PMID: 39733900 DOI: 10.1016/j.ijbiomac.2024.139117
Abstract

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and transcription. CDK7 plays a pivotal role in cell division and proliferation, and the CDK7 gene often exhibits mutations or copy number loss in Cancer. Pharmacological targeting of CDK7 has been proposed as a Cancer treatment strategy and several inhibitors are currently in clinical trials. As opposed to CDK2, the use of structure-assisted drug design for CDK7 has been limited. We present here CDK2m7, a CDK2-based CDK7 mimic created by mutagenesis of the CDK2 active site pocket. CDK2m7 can be produced in E. coli in a fully active complex with cyclin A2 in high yield and purity. CDK2m7 exhibits a shift in inhibitor selectivity from CDK2 to CDK7 and readily crystallizes. Therefore, it can be used in structure-assisted design of CDK7 inhibitors, as demonstrated by the crystal structure of the complex with inhibitor SY5609. CDK2m7 thus represents a simple and affordable platform for CDK7 rational drug development.

Keywords

Cyclin-dependent kinase; Inhibitor; SY5609; Selectivity; Structure-assisted inhibitor design; X-ray crystallography.

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