Bioorganic & medicinal chemistry letters, 2013-06, Vol.23 (11), p.3149-3153
2013
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design
- Ist Teil von
- Bioorganic & medicinal chemistry letters, 2013-06, Vol.23 (11), p.3149-3153
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2013
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0960-894XeISSN: 1464-3405DOI: 10.1016/j.bmcl.2013.04.020Titel-ID: cdi_proquest_miscellaneous_1350153947
- Format
- –
- Schlagworte
- adenosine triphosphate, Animals, Binding Sites, Cell Line, Cell Survival - drug effects, chemistry, Crystallography, X-Ray, Drug Design, Drug Evaluation, Preclinical, drugs, High throughput screening, Humans, Kinase inhibitor, Kinetics, Lead optimization, Mice, myeloma, phosphotransferases (kinases), Pim kinases, Protein Isoforms - antagonists & inhibitors, Protein Isoforms - metabolism, Protein Kinase Inhibitors - chemical synthesis, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Protein Structure, Tertiary, Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 - metabolism, Pyrazoles - chemical synthesis, Pyrazoles - chemistry, Pyrazoles - pharmacology, pyrimidines, Pyrimidines - chemical synthesis, Pyrimidines - chemistry, Pyrimidines - pharmacology, screening, Structure based drug design, Structure-Activity Relationship, therapeutics