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Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Dec 15; Vol. 22 (24), pp. 7615-22. Date of Electronic Publication: 2012 Oct 11. - Publication Year :
- 2012
-
Abstract
- A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 μM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 μM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents administration & dosage
Antineoplastic Agents chemistry
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mice
Models, Molecular
Molecular Structure
Neoplasms, Experimental pathology
Protein Kinase Inhibitors administration & dosage
Protein Kinase Inhibitors chemistry
Structure-Activity Relationship
Polo-Like Kinase 1
Antineoplastic Agents pharmacology
Cell Cycle Proteins antagonists & inhibitors
High-Throughput Screening Assays
Neoplasms, Experimental drug therapy
Protein Kinase Inhibitors pharmacology
Protein Serine-Threonine Kinases antagonists & inhibitors
Proto-Oncogene Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23103095
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.10.009