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New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia
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SYSNO ASEP 0521912 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title New 2,6,9-trisubstituted purine derivatives as Bcr-Abl and Btk inhibitors and as promising agents against leukemia Author(s) Bertrand, J. (CL)
Dostálová, Hana (UEB-Q)
Kryštof, Vladimír (UEB-Q) RID, ORCID
Jorda, Radek (UEB-Q) ORCID, RID
Castro, A. (ES)
Mella, J. (CL)
Espinosa-Bustos, C. (CL)
María Zarate, A. (CL)
Salas, C. O. (CL)Number of authors 9 Article number 103361 Source Title Bioorganic Chemistry. - : Elsevier - ISSN 0045-2068
Roč. 94, JAN (2020)Number of pages 11 s. Language eng - English Country US - United States Keywords Bcr-Abl inhibitors ; Btk inhibitors ; Docking ; Leukemia ; Purine derivatives ; qsar Subject RIV FD - Oncology ; Hematology OECD category Technologies involving identifying the functioning of DNA, proteins and enzymes and how they influence the onset of disease and maintenance of well-being (gene-based diagnostics and therapeutic interventions (pharmacogenomics, gene-based therapeutics) Method of publishing Open access Institutional support UEB-Q - RVO:61389030 UT WOS 000505596300019 EID SCOPUS 85075434817 DOI 10.1016/j.bioorg.2019.103361 Annotation Bcr-Abl and Btk kinases are among the targets that have been considered for the treatment of leukemia. Therefore, several strategies have focused on the use of inhibitors as chemotherapeutic tools to treat these types of leukemia, such as imatinib (for Bcr-Abl) or ibrutinib (for Btk). However, the efficacy of these drugs has been reduced due to resistance mechanisms, which have motivated the development of new and more effective compounds. In this study, we designed, synthesized and evaluated 2,6,9-trisubstituted purine derivatives as novel Bcr-Abl and Btk inhibitors. We identified 5c and 5d as potent inhibitors of both kinases (IC50 values of 40 nM and 0.58/0.66 μM for Abl and Btk, respectively). From docking and QSAR analyses, we concluded that fluorination of the arylpiperazine system is detrimental to the activity against two kinases, and we also validated our hypothesis that the substitution on the 6-phenylamino ring is important for the inhibition of both kinases. In addition, our studies indicated that most compounds could suppress the proliferation of leukemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos cells) at low micromolar concentrations in vitro. Finally, we preliminarily demonstrated that 5c inhibited the downstream signaling of both kinases in the respective cell models. Therefore, 5c or 5d possessed potency to be further optimized as anti-leukemia drugs by simultaneously inhibiting the Bcr-Abl and Btk kinases. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2020 Electronic address http://dx.doi.org/10.1016/j.bioorg.2019.103361
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