1.
Bioorg Med Chem Lett
; 30(23): 127625, 2020 12 01.
Article
in English
| MEDLINE
| ID: mdl-33096160
ABSTRACT
N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subsequently impacted KG-1 tumor growth in a mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Mice , Piperidines/chemical synthesis , Piperidines/metabolism , Piperidines/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Rats , Stereoisomerism , Xenograft Model Antitumor Assays
2.
Bioorg Med Chem Lett
; 29(3): 491-495, 2019 02 01.
Article
in English
| MEDLINE
| ID: mdl-30553737
ABSTRACT
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.
