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.
Keywords:
AML; Cancer; Lead; PK/PD; Pan-PIM kinases; Tumor growth inhibition.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Antineoplastic Agents / administration & dosage
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
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*
-
Mice
-
Molecular Structure
-
Neoplasms, Experimental / drug therapy
-
Neoplasms, Experimental / metabolism
-
Neoplasms, Experimental / pathology
-
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
Substances
-
7-azaindole dimer
-
Antineoplastic Agents
-
Indoles
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins c-pim-1
-
proto-oncogene proteins pim