1.
Bioorg Med Chem Lett
; 20(15): 4587-92, 2010 Aug 01.
Article
in English
| MEDLINE
| ID: mdl-20594842
ABSTRACT
Potent inhibitors of PLK1 with acceptable solubility, mouse iv clearance, and reduced CYP450 inhibition were identified. Drug-like properties were improved using a heteroaryl ring as a functional handle for manipulation of inhibitors' physiochemical and DMPK properties.
Subject(s)
Amides/chemistry , Antineoplastic Agents/chemistry , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Computer Simulation , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Humans , Injections, Intravenous , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Structure-Activity Relationship , Thiophenes/chemistry , Polo-Like Kinase 1
2.
Bioorg Med Chem Lett
; 19(6): 1694-7, 2009 Mar 15.
Article
in English
| MEDLINE
| ID: mdl-19237286
ABSTRACT
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and PLK3 was also obtained through these modifications.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiophenes/chemistry , Cell Cycle , Cell Cycle Proteins/chemistry , Cell Line, Tumor , Drug Design , Humans , Inhibitory Concentration 50 , Mitosis , Models, Chemical , Molecular Conformation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Solubility , Tumor Suppressor Proteins , Polo-Like Kinase 1
3.
Bioorg Med Chem Lett
; 19(3): 1018-21, 2009 Feb 01.
Article
in English
| MEDLINE
| ID: mdl-19097784
ABSTRACT
The discovery and development of a series of thiophenes as potent and selective inhibitors of PLK is described. Identification and characterization of 2, a useful in vitro PLK inhibitor tool compound, is also presented.
