1. Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors.
- Author
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Zhang Q, Xia Z, Mitten MJ, Lasko LM, Klinghofer V, Bouska J, Johnson EF, Penning TD, Luo Y, Giranda VL, Shoemaker AR, Stewart KD, Djuric SW, and Vasudevan A
- 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
- 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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