ABSTRACT
KRASG12D, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRASG12C, selective inhibition of KRASG12D presents a significant challenge due to the requirement of inhibitors to bind KRASG12D with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRASG12D inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRASG12D mutant xenograft mouse tumor model.
Subject(s)
Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Drug Discovery , Humans , Mice , Models, Molecular , Mutation , Proto-Oncogene Proteins p21(ras)/genetics , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.
Subject(s)
Antineoplastic Agents/pharmacology , Indazoles/pharmacology , Leukemia, Myeloid, Acute/pathology , Myelodysplastic Syndromes/pathology , Receptor, TIE-2/antagonists & inhibitors , Urea/analogs & derivatives , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Angiopoietin-1/metabolism , Animals , Cell Line, Tumor , Drug Screening Assays, Antitumor , Gene Knockdown Techniques , Humans , Male , Mice , Proportional Hazards Models , Urea/pharmacologyABSTRACT
A series of oxazole-substituted indanylacetic acids were prepared which show a spectrum of activity as ligands for PPAR nuclear receptor subtypes.
Subject(s)
Acetates/pharmacology , Oxazoles/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Acetates/administration & dosage , Acetates/chemical synthesis , Administration, Oral , Animals , Blood Glucose/drug effects , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Drug Evaluation, Preclinical , Ligands , Mice , Mice, Mutant Strains , Mice, Obese , Molecular Structure , PPAR alpha/metabolism , PPAR gamma/metabolism , Structure-Activity Relationship , Triglycerides/blood , Triglycerides/metabolismABSTRACT
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes.
