ABSTRACT
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.
Subject(s)
Antineoplastic Agents/therapeutic use , Multiple Myeloma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Pyrazoles/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Line, Tumor , Dogs , Female , Humans , Macaca fascicularis , Madin Darby Canine Kidney Cells , Male , Mice, SCID , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.
Subject(s)
Bile Acids and Salts/chemistry , Fatty Acid-Binding Proteins/chemistry , Gastrointestinal Hormones/chemistry , Binding Sites , Crystallography, X-Ray , Fatty Acid-Binding Proteins/antagonists & inhibitors , Gastrointestinal Hormones/antagonists & inhibitors , Humans , Models, Molecular , Protein Conformation , Structure-Activity Relationship , Surface Plasmon Resonance , Taurocholic Acid/chemistryABSTRACT
MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
