ABSTRACT
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Oral , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , Haplorhini , Humans , Lung Neoplasms/drug therapy , Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolismABSTRACT
Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) proliferation inhibitors from a cell-based high-throughput screening (HTS), we eliminated those compounds which showed cytotoxicity against HCT116 and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitory activity. Evaluations in human Calu-6 xenograft model delivered lead compound 1. Following extensive lead optimization and alteration of the scaffold we discovered 32f and 32g, which both inhibited the proliferation and tube formation of HUVEC without showing inhibitory activity against any of 25 kinases or cytotoxicity against either normal fibroblasts or 40 cancer cell lines. Upon oral administration, 32f and 32g had good pharmacokinetic profiles and potent antitumor activity and decreased microvessel density (MVD) in Calu-6 xenograft model. Combination therapy with a VEGFR inhibitor enhanced the in vivo efficacy. These results suggest that 32f and 32g may have potential for use in cancer treatment.
Subject(s)
Angiogenesis Inhibitors , Benzyl Compounds/chemistry , Endothelial Cells/drug effects , Phenyl Ethers/chemistry , Angiogenesis Inhibitors/chemical synthesis , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Benzyl Compounds/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Phenyl Ethers/pharmacology , Structure-Activity Relationship , Styrenes/chemical synthesis , Styrenes/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbazoles/chemical synthesis , Piperazines/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Carbazoles/pharmacokinetics , Carbazoles/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Female , Humans , In Vitro Techniques , Macaca fascicularis , Male , Mice , Mice, SCID , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivatives as potent ALK inhibitors. Among them, compound 27 showed strong cytotoxicity against KARPAS-299 with an IC(50) value of 21 nM and significant antitumor efficacy in ALK fusion-positive blood and solid cancer xenograft models in mice without body weight loss.
Subject(s)
Antineoplastic Agents/chemical synthesis , Drug Discovery , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Tetracyclines/chemical synthesis , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Disease Models, Animal , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Tetracyclines/chemistry , Tetracyclines/pharmacologyABSTRACT
The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
Subject(s)
Antineoplastic Agents/chemistry , Benzamides/chemistry , MAP Kinase Kinase Kinases/antagonists & inhibitors , Oxazines/chemistry , Protein Kinase Inhibitors/chemistry , Administration, Oral , Allosteric Regulation , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Benzamides/administration & dosage , Benzamides/pharmacology , Humans , Models, Molecular , Oxazines/administration & dosage , Oxazines/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacologyABSTRACT
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.
