Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma.
Animals
Antineoplastic Agents
/ chemical synthesis
Cell Line, Tumor
Dogs
Female
Humans
Macaca fascicularis
Madin Darby Canine Kidney Cells
Male
Mice, SCID
Molecular Structure
Multiple Myeloma
/ drug therapy
Protein Binding
Protein Kinase Inhibitors
/ chemical synthesis
Proto-Oncogene Proteins c-pim-1
/ antagonists & inhibitors
Pyrazoles
/ chemical synthesis
Rats, Sprague-Dawley
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
28 02 2019
28 02 2019
Historique:
pubmed:
5
2
2019
medline:
4
3
2020
entrez:
5
2
2019
Statut:
ppublish
Résumé
Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.
Identifiants
pubmed: 30715878
doi: 10.1021/acs.jmedchem.8b01857
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Pyrazoles
0
PIM1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-pim-1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM