Design,Synthesis And Preliminary Biological Evaluation Of BTK/HDAC Dual Target Inhibitors

Because of the nature of this malignant tumors that usually involves complex pathogenesis,combination therapy may potentiate efficacy in a synergistic or additive manner,which is becoming an effective practice in cancer treatment.However,poor pharmacokinetic changes or unexpected toxicity limit the application of combination drugs.Multi-target drugs can not only play a synergistic effect on multiple pathogenesis,but reduce adverse drug reactions.BTK kinase is a member of the Tec kinase family that has been reported to be most related to human diseases.BTK is expressed in most hematopoietic system cells,especially in B cells,myeloid cells and platelets.Meanwhile,BTK is specifically required for BCR signaling pathway,which is critical for the proliferation,differentiation and apoptosis in B cell lymphoma.The FDA-approved first-in-class irreversible BTK inhibitor in 2013,ibrutinib,is effective in clinical treatment.However,due to the adverse reactions aused by off-target and drug resistance,it is promising to develop BTK inhibitors.The epigenetic regulator HD AC can catalyze the acetylation of lysine residues on histones and other proteins,thereby regulating chromatin structure and transcriptional activity,involving different pathological states.HDACi can inhibit cyclin D1 protein expression,regulate p53 expression and NF-κB activity,thereby blocking PI3K/AKT/mTOR and NF-κB signaling pathways.In addition,HDAC regulates the binding ability of HSP90 to drug-resistant mutant protein and increases the stability of the mutant protein.This provides theoretical basis for solving the primary and secondary ibrutinibresistance.At present,the combined drug experiment of HDAC inhibitor and BTK inhibitor has shown a good synergistic inhibitory effect on a variety of lymphomas.Based on our laboratory had designed and synthesized the multiple series of dualtarget inhibitors,the paper retains the 4-aminopyrazolopyrimidine core,with 4phenoxyphenyl or pyridylamino phenyl structure as the hydrophobic group,and Ophenylenediamine as the ZBG group,while optimizing Linker,the ZH series of compounds were designed and synthesized.22 new compounds were synthesized and characterized.This thesis evaluated the in vitro activity of the series of compounds.At 1 μM,most of the compounds showed a strong inhibitory effect on BTK kinase.In the HDACs inhibitory activity experiment,with the optimization of Linker,some compounds showed moderate inhibitory strength.With the optimization of Linker,some compounds showed moderate inhibition strength.In the in vitro cell anti-proliferative activity test,there are many compounds that have stronger or equivalent inhibitory ability to Jeko-1 than IBN(IC50=4.706 ± 0.016 μM).The compound ZH24(IC50=1.416 ± 0.050 μM),which has dual-target inhibitory potential,also exhibits inhibitory activity on other cells,(HEL IC50=25.320 ± 1.19 μM;K562 IC50=2.098±0.004 μM).This paper explores the dual-targeted drugs that simultaneously target BTK and HDAC and lays the foundation for research.It is expected that multiple carcinogenic pathways can be targeted at the same time to solve clinical drug resistance and reduce adverse reactions caused by drug combination.