ABSTRACT
The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC(50) values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Quinolines/chemistry , src-Family Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Humans , Mice , Mice, Nude , Microsomes/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Xenograft Model Antitumor Assays , src-Family Kinases/metabolismABSTRACT
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cysteine/metabolism , Lactones/chemical synthesis , Oncogene Protein v-akt/antagonists & inhibitors , Pyrans/chemical synthesis , Alkylation , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Biomarkers/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Lactones/chemistry , Lactones/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Pyrans/chemistry , Pyrans/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Checkpoint deficiency of malignant cells can be exploited in cancer drug discovery. Compounds that selectively kill checkpoint-deficient cells versus checkpoint-proficient cells can be utilized to preferentially target tumor cells, while sparing normal cells. The protein p21(Wafl/Cipl/Sdi1) (hereafter referred to as p21) inhibits progression of the cell cycle by inhibiting the activity of G1 kinases (cyclin D/cdk4 and cyclin E-cdk2) and the G2 kinase (cyclin B/cdkl) in response to DNA damage or abnormal DNA content. The expression of p21 is often low in human cancer cells due to frequent loss of the upstream activator, p53, and is associated with poor prognosis in some cancer patients. Using an isogenic pair of cell lines, HCT116 (p21+/+) and 80S14 (p21-/-), we have disclosed previously a novel series of pyrazolo[1,5-a]pyrimidines that preferentially kill the p21-deficient cells. We will present the synthesis, biological activities and SAR study of a series of pyrazolo[1,5-a]pyrimidines with an optimized phenyl amide moiety at the C-7 position. The mechanism of action of these compounds will also be discussed.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrazoles/chemistry , Pyrimidines/chemistry , Amides/chemistry , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 4/metabolism , Humans , Mice , Mice, Nude , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
New 4-phenylamino-3-quinolinecarbonitriles with a 7-ethynyl group substituted by a pyridine, phenyl or thiophene ring containing basic water solubilizing groups were prepared and evaluated as Src kinase inhibitors. Of these new analogs, potent activity was observed with compounds having a (2,4-dichloro-5-methoxyphenyl)amino group at C-4, a methoxy or ethoxy group at C-6, and a pyridyl group bearing a dimethylamine or N-methylpiperazine on the ethynyl group at C-7.
Subject(s)
Quinolines/pharmacology , Water/chemistry , src-Family Kinases/antagonists & inhibitors , Quinolines/chemistry , SolubilityABSTRACT
A novel series of p21 chemoselective agents containing a pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides were identified by high throughput screening. Optimization of the amide region by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described. The isopropyl carbamate derivative 34 was identified as a highly chemoselective agent displaying a potency of 51 nM in the p21 deficient cell line.
