Discovery of N-substituted 7-azaindoles as Pan-PIM kinases inhibitors – Lead optimization – Part III

[Display omitted] N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 sh...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-02, Vol.29 (3), p.491-495
Main Authors: Barberis, Claude, Pribish, James, Tserlin, Elina, Gross, Alexandre, Czekaj, Mark, Barragué, Matthieu, Erdman, Paul, Maniar, Sachin, Jiang, John, Fire, Luke, Patel, Vinod, Hebert, Andrew, Levit, Mikhail, Wang, Anlai, Sun, Frank, Huang, Shih-Min A.
Format: Article
Language:English
Subjects:
AML
Animals
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cancer
Cell Line, Tumor
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Humans
Indoles - administration & dosage
Indoles - chemistry
Indoles - pharmacology
Lead
Mice
Molecular Structure
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - metabolism
Neoplasms, Experimental - pathology
Pan-PIM kinases
PK/PD
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 - metabolism
Rats
Structure-Activity Relationship
Tumor growth inhibition
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Summary:[Display omitted] N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.12.015