ABSTRACT
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.
Subject(s)
ErbB Receptors , Lung Neoplasms , Niacinamide , Humans , Drug Resistance, Neoplasm , ErbB Receptors/drug effects , ErbB Receptors/genetics , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship , /pharmacology , Niacinamide/analogs & derivatives , Niacinamide/chemistryABSTRACT
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.
Subject(s)
Antineoplastic Agents , ErbB Receptors , Mutation , Protein Kinase Inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Humans , Administration, Oral , Animals , Structure-Activity Relationship , Mice , Drug Discovery , Molecular Docking Simulation , Molecular Structure , Cell Line, Tumor , Drug Screening Assays, Antitumor , Cell Proliferation/drug effectsABSTRACT
Histone acetyltransferases (HATs) play a crucial role in post-translational modification. Among them, overexpression, mutation, or hyperfunction of EP300/CBP has been associated with various cancers. In this study, we identified the novel compound 2-chloro-5-[5-[(E)-[1-(3-chlorophenyl)-3-methyl-5-oxo-pyrazol-4-ylidene]methyl]-2-furyl]benzoic acid (1) as an EP300 HAT inhibitor via virtual screening. Further research has been focused on the design, synthesis, and in vitro biological evaluation of virtual hit derivatives. The studies revealed that 4-pyridone-3-carboxylic acid derivatives exhibited bioisosterism of benzoic acid. Replacement proved effective, providing compounds with similar EP300 HAT-inhibitory activity and improved cell growth-inhibitory activity compared to the benzoic acid analogs. Through these studies, we identified a potent and selective EP300/CBP HAT inhibitor.
Subject(s)
Antineoplastic Agents/pharmacology , Benzoic Acid/pharmacology , Drug Design , E1A-Associated p300 Protein/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Peptide Fragments/antagonists & inhibitors , Sialoglycoproteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzoic Acid/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , E1A-Associated p300 Protein/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Peptide Fragments/metabolism , Sialoglycoproteins/metabolism , Structure-Activity RelationshipABSTRACT
BACKGROUND: TZT-1027 (Soblidotin), a newly synthesized dolastatin 10 derivative that depolymerizes microtubules, has potent antitumor activity. MATERIALS AND METHODS: Cell-killing kinetic analysis was performed by the colony-forming assay and the kinetics of TZT-1027 were compared with those of neocarzinostatin, adriamycin and vincristine, known to be typical concentration-, AUC- and time-dependent agents, respectively. DNA fragmentation was detectable by electrophoresis, cytotoxicity was evaluated by MTT assay and antitumor activity was examined by measuring the tumor weight after treatment. RESULTS: TZT-1027 exhibited its cytocidal and apoptosis-inducing activity in a time-dependent manner. Its growth-inhibitory effect was less affected by overexpression of P-glycoprotein than that of other tubulin inhibitors and was not affected by the overexpression of breast cancer resistance protein or multidrug resistance-associated protein. TZT-1027 exhibited potent antitumor activities in an in vivo tumor model in which vincristine and docetaxel failed to show effectiveness. CONCLUSION: Because its growth-inhibitory and antitumor activities were superior to those of the other drugs tested, including the tubulin inhibitors paclitaxel, docetaxel and vincristine, TZT-1027 should be useful in the chemotherapy of tumors that are not responsive to other tubulin inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Oligopeptides/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/metabolism , Animals , Antineoplastic Agents/pharmacokinetics , Cell Death/drug effects , Cell Death/physiology , Cell Growth Processes/drug effects , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , DNA Fragmentation/drug effects , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Fibrosarcoma/drug therapy , Fibrosarcoma/metabolism , Fibrosarcoma/pathology , Humans , Male , Mice , Mice, Inbred BALB C , Multidrug Resistance-Associated Proteins/biosynthesis , Multidrug Resistance-Associated Proteins/metabolism , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/metabolism , Oligopeptides/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes and related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in vitro and in vivo antitumor activity against some tumor models when administered both intraperitoneally and orally. Compounds with the 3-chloropyridin-2-yl group (9g) and the 3-fluoro-5-substituted phenylpiperazinyl group (29b, c, and e) showed significantly potent cytotoxicity by in vitro testing. Among them, the 3-cyano-5-fluorophenyl derivative (29b) exhibited potent antitumor activity against several tumor cells including human carcinoma without causing undesirable effects in mice.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Propane/analogs & derivatives , Propane/chemical synthesis , Propane/pharmacology , Animals , Cell Line, Tumor , Chemical Phenomena , Chemistry, Physical , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Structure-Activity RelationshipABSTRACT
Pyrimidinyl pyrazole derivatives 1-4, prepared as a new scaffold of an anti-tumor agent, showed antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization. Furthermore, it was found that compound 2 bound at the colchicine site on tubulin, but the tubulin binding pattern was different from that of colchicine. Here, we describe the synthesis of the derivatives and the differences of the action mechanism on tubulin polymerization inhibition between compound 2 and colchicine.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Binding, Competitive/drug effects , Colchicine/pharmacology , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Microtubules/drug effects , Protein Binding/drug effects , Tubulin/drug effects , Tubulin Modulators , Tumor Cells, CulturedABSTRACT
A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.