ABSTRACT
CDK8 is a transcriptional cyclin-dependent kinase and considered as a potential target in colon cancer therapeutics. Here, a novel selective CDK8 inhibitor was identified against colon cancer in vivo. Specifically, based on the structural information of the sorafenib-bound CDK8 structure, a series of novel 2-amino-pyridine derivatives were designed, synthesized, and evaluated. Among them, compound 29 showed strong inhibitory activity against CDK8 with an IC50 value of 46 nM and favorable selectivity. And there is an apparent interaction between the endogenous or overexpressed CDK8 and biotinylated-29. This compound exhibited antiproliferation potency on colon cancer cell lines with a high CDK8 expression level, suppressed the activation of WNT/ß-catenin and transcriptional activity of the TCF family, and induced G1 phase arrested in HCT-116 cells. In addition, this compound showed potent activity against sorafenib-resistant HCT-116 cells. What's more, it exhibited low toxicity and suitable pharmacokinetic (PK) profiles and showed preferable antitumor effects in vivo.
Subject(s)
Colonic Neoplasms , beta Catenin , Cell Line, Tumor , Colonic Neoplasms/pathology , Cyclin-Dependent Kinase 8 , Cyclin-Dependent Kinases/metabolism , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Sorafenib , beta Catenin/metabolismABSTRACT
Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.
Subject(s)
Anti-Inflammatory Agents/chemistry , Cathepsin C/antagonists & inhibitors , Drug Discovery , Protease Inhibitors/chemistry , Anti-Inflammatory Agents/therapeutic use , COVID-19/pathology , COVID-19/virology , Cathepsin C/genetics , Cathepsin C/metabolism , Humans , Papillon-Lefevre Disease/genetics , Papillon-Lefevre Disease/pathology , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/isolation & purification , Serine Endopeptidases/metabolism , COVID-19 Drug TreatmentABSTRACT
Basis on molecular docking and pharmacophore analysis of naphthoquinone moiety, a total of 23 compounds were designed and synthesised. With the help of reverse targets searching, anti-cancer activity was preliminarily evaluated, most of them are effective against some tumour cells, especially compound 12: 1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl-4-oxo-4-((4-phenoxyphenyl)amino) butanoate whose IC50 against SGC-7901 was 4.1 ± 2.6 µM. Meanwhile the anticancer mechanism of compound 12 had been investigated by AnnexinV/PI staining, immunofluorescence, Western blot assay and molecular docking. The results indicated that this compound might induce cell apoptosis and cell autophagy through regulating the PI3K signal pathway.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Naphthoquinones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A major goal of medicinal chemists is to identify and validate novel and effective kinase targets for treatment of cancer. Recent studies have shown that cyclin-dependent kinase 8 (CDK8) is a target for treatment of colorectal, breast, melanoma, and prostate cancers. The crystal structure of CDK8 has been reported, and eutectic interactions have been identified for 24 compounds that target CDK8. To more effectively develop CDK8 inhibitors, particularly those with improved selectivity, we summarized the structure, structure-activity relationships, and binding information of typical CDK8 inhibitors, which may serve as a reference for development of novel CDK8 inhibitors.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinase 8/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Cyclin-Dependent Kinase 8/chemistry , Cyclin-Dependent Kinase 8/metabolism , Drug Discovery , Humans , Models, Molecular , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/metabolism , Structure-Activity RelationshipABSTRACT
Eleven dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)naphthalene derivatives as anticancer agents through regulating cell autophagy were designed and synthesized. The anticancer activity results indicated that most compounds manifested obvious un-toxic effect on GES-1 and L-02 with IC50 from 0.58 to 1.41 mM. Among them, (S,Z)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 4-(3,4- dihydroisoquinolin-2(1 H)-yl)-4-oxobut-2-enoate (compound 4i) could induce cancer cells apoptosis. Further experiments showed that autophagy played an important role in the pro-apoptotic effect of this compound. Preliminary mechanism indicated that this compound could inhibit phosphoinositide 3-kinase/protein kinase B and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway by mediating apoptosis in an autophagy-dependent manner.
Subject(s)
Antineoplastic Agents/pharmacology , Autophagy/drug effects , Naphthalenes/pharmacology , Neoplasms/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Drug Design , Humans , Inhibitory Concentration 50 , Naphthalenes/chemical synthesis , Naphthalenes/chemistry , Neoplasms/pathology , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolismABSTRACT
The direct C-H bond arylation of (benzo)oxazoles with aryl chlorides was achieved catalyzed by a well-defined NHC-Pd(II)-Im complex. Under the optimal conditions, various aryl chlorides were successfully applied as the arylating reagents to achieve the 2-aryl (benzo)oxazoles in acceptable to high yields, providing a convenient and alternative method for the direct C-H bond arylation of (benzo)oxazoles and enriching the chemistry of the NHC-Pd(II) complex in organic synthesis.