AI Article Synopsis
- The study explores a hybridization strategy for developing multi-target inhibitors in drug design, focusing on combining the pharmacophores of momelotinib and tandutinib.
- A series of derivatives were created and tested for their ability to inhibit JAK2 and FLT3 enzymes, with several compounds also evaluated for their effectiveness against specific cancer cell lines.
- Compound 14j emerged as the most potent dual inhibitor, effectively inducing apoptosis and halting the cell cycle in the G/S phase, demonstrating strong potential in cancer treatment.
Article Abstract
Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the "A" phenyl ring and "B" phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC = 27 nM, FLT3 IC = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.
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| http://dx.doi.org/10.1016/j.ejmech.2019.111590 | DOI Listing |
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