Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors - Part I

Claude Barberis; Neil Moorcroft; Chris Arendt; Mikhail Levit; Sandra Moreno-Mazza; Joseph Batchelor; Ingrid Mechin; Tahir Majid

doi:10.1016/j.bmcl.2017.08.069

Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors - Part I

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4730-4734. doi: 10.1016/j.bmcl.2017.08.069. Epub 2017 Sep 18.

Authors

Claude Barberis¹, Neil Moorcroft², Chris Arendt³, Mikhail Levit³, Sandra Moreno-Mazza³, Joseph Batchelor⁴, Ingrid Mechin⁴, Tahir Majid⁵

Affiliations

¹ IDD Medicinal Chemistry, Sanofi Genzyme, 153 Second Avenue, Waltham MA 02451, USA. Electronic address: claude.barberis2@sanofi.com.
² IDD Medicinal Chemistry, Sanofi Genzyme, 153 Second Avenue, Waltham MA 02451, USA.
³ Oncology Biochemistry/Biology, Sanofi Genzyme, 270 Albany Street, Cambridge, MA 02139, USA.
⁴ IDD In Vitro Biology, Sanofi, 153 Second Avenue, Waltham MA 02451, USA.
⁵ IDD Medicinal Chemistry, Sanofi Genzyme, 153 Second Avenue, Waltham MA 02451, USA; Program Management, Sanofi Genzyme, 49 New York Avenue, Framingham MA 01701, USA.

PMID: 28947155
DOI: 10.1016/j.bmcl.2017.08.069

Abstract

Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.

Keywords: Cancer; Inhibitors; PIM1; X-ray crystallography.

MeSH terms

Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Humans
Indoles / chemistry*
Indoles / metabolism
Indoles / pharmacology*
Inhibitory Concentration 50
Molecular Dynamics Simulation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / metabolism
Protein Structure, Tertiary
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
Proto-Oncogene Proteins c-pim-1 / metabolism
Structure-Activity Relationship

Substances

7-azaindole dimer
Indoles
PIM2 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins
PIM3 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-pim-1