ABSTRACT
The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Ataxia Telangiectasia Mutated Proteins/metabolism , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Phosphatidylinositol 3-Kinases/chemistry , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/metabolism , Pyridines/metabolism , Pyrimidines/metabolismABSTRACT
The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22ß-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKß inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKß in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC50 of 0.98 µM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKß.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Lung Neoplasms/drug therapy , NF-kappa B/metabolism , Oleanolic Acid/analogs & derivatives , Tumor Necrosis Factor-alpha/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Molecular Docking Simulation , Molecular Structure , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Structure-Activity RelationshipABSTRACT
A simple and economical method was developed for the extraction and isolation of pentacyclic triterpenoid lantadene A from the leaves of Lantana camara. The lantadene A displays significant anti-inflammatory and anticancer properties via the inhibition of IKK-mediated NF-κB protein. Therefore, the derivatives of lantadene A were synthesised to further optimise the pharmacophore for anti-inflammatory and anticancer activities. The synthesised compounds were docked into the active site of IKK to find the most potent inhibitor of IKK. Molecular docking studies revealed that 3ß,22ß-diisobutyl substituted lantadene derivative (10) binds to the IKK protein with the highest affinity. Furthermore, in the in silico ADMET studies, the lead IKK inhibitor (10) was found to be Ames non-toxic, non-carcinogen, and a weak inhibitor of hERG.[Figure: see text].