ABSTRACT
Reactivating p53 activity to restore its anticancer function is an attractive cancer treatment strategy. In this study, we designed and synthesized a series of novel PROTACs to reactivate p53 via the co-degradation of CK1α and CDK7/9 proteins. Bioactivity studies showed that the selected PROTAC 13i exhibited potency antiproliferative activity in MV4-11 (IC50 = 0.096 ± 0.012 µM) and MOLM-13 (IC50 = 0.072 ± 0.014 µM) cells, and induced apoptosis of MV4-11 cells. Western-blot analysis showed that PROTAC 13i triple CK1α and CDK7/9 protein degradation resulted in the significantly increased expression of p53. At the same time, the transcriptional repression due to the degradation significantly reduced downstream gene expression of MYC, MDM2, BCL-2 and MCL-1, and reduced the inflammatory cytokine levels of TNF-α, IL-1ß and IL-6 in PMBCs. These results indicate the beneficial impact of simultaneous CK1α and CDK7/9 degradation for acute myeloid leukemia therapy.
Subject(s)
Antineoplastic Agents , Casein Kinase Ialpha , Cell Proliferation , Cyclin-Dependent Kinase 9 , Cyclin-Dependent Kinases , Drug Screening Assays, Antitumor , Leukemia, Myeloid, Acute , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Casein Kinase Ialpha/metabolism , Casein Kinase Ialpha/antagonists & inhibitors , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Cyclin-Dependent Kinase 9/metabolism , Structure-Activity Relationship , Molecular Structure , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/metabolism , Dose-Response Relationship, Drug , Apoptosis/drug effects , Drug Discovery , Cell Line, Tumor , Proteolysis/drug effects , Tumor Cells, Cultured , Proteolysis Targeting Chimera , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
In the current study, we designed and synthesised a novel series of 2-(2,6-dioxopiperidin-3-yl)isoquinoline-1,3(2H,4H)-dione derivatives as cereblon (CRBN) modulators. The results of the CCK8 assay revealed potent antiproliferative activity for the selected compound 10a against NCI-H929 (IC50=2.25 µM) and U239 (IC50=5.86 µM) cell lines. Compound 10a also can inhibit the TNF-α level (IC50=0.76 µM) in LPS stimulated PMBC and showed nearly no toxicity to this normal human cell line. The TR-FRET assay showed compound 10a having potent inhibitory activity against CRBN (IC50=4.83 µM), and the docking study confirmed a nice fitting of 10a into the active sites of CRBN. Further biology studies revealed compound 10a can increase the apoptotic events, arrest the NCI-H929 cells at G0/G1 cell cycle, and induce the ubiquitination degradation of IKZF1 and IKZF3 proteins by CRL4CRBN. These preliminary results suggested that compound 10a could serve as a potential antitumor drug and worthy of further investigation.
