Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors

0523373 - ÚOCHB 2021 RIV GB eng J - Journal Article
Köprülüoglu, Cemal - Dejmek, Milan - Šála, Michal - Ajani, Haresh - Hřebabecký, Hubert - Fanfrlík, Jindřich - Jorda, Radek - Dračínský, Martin - Procházková, Eliška - Šácha, Pavel - Kryštof, Vladimír - Hobza, Pavel - Lepšík, Martin - Nencka, Radim
Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors.
Journal of Molecular Recognition. Roč. 33, č. 8 (2020), č. článku e2842. ISSN 0952-3499. E-ISSN 1099-1352
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963 ; RVO:61389030
Keywords : ATP-competitive type I inhibitors * cyclin-dependent kinase 2 * protein-ligand binding * quantum mechanical scoring
OECD category: Physical chemistry
Impact factor: 2.137, year: 2020
Method of publishing: Limited access
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmr.2842

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin‐dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.
Permanent Link: http://hdl.handle.net/11104/0307732