ABSTRACT
Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.
Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Isocitrate Dehydrogenase/antagonists & inhibitors , Neoplasms/drug therapy , Pyridines/therapeutic use , Quinolines/therapeutic use , Quinolones/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Female , Humans , Isocitrate Dehydrogenase/metabolism , Mice, Inbred BALB C , Molecular Structure , Protein Binding , Pyridines/chemical synthesis , Pyridines/metabolism , Quinolines/chemical synthesis , Quinolines/metabolism , Quinolones/chemical synthesis , Quinolones/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.
Subject(s)
Drug Discovery , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
Mutations at the arginine residue (R132) in isocitrate dehydrogenase 1 (IDH1) are frequently identified in various human cancers. Inhibition of mutant IDH1 (mIDH1) with small molecules has been clinically validated as a promising therapeutic treatment for acute myeloid leukemia and multiple solid tumors. Herein, we report the discovery and optimization of a series of quinolinones to provide potent and orally bioavailable mIDH1 inhibitors with selectivity over wild-type IDH1. The X-ray structure of an early lead 24 in complex with mIDH1-R132H shows that the inhibitor unexpectedly binds to an allosteric site. Efforts to improve the in vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) properties of 24 yielded a preclinical candidate 63. The detailed preclinical ADME and pharmacology studies of 63 support further development of quinolinone-based mIDH1 inhibitors as therapeutic agents in human trials.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isocitrate Dehydrogenase/antagonists & inhibitors , Quinolones/chemistry , Quinolones/pharmacology , Allosteric Site/drug effects , Animals , Biological Availability , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Drug Discovery , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Isocitrate Dehydrogenase/chemistry , Isocitrate Dehydrogenase/genetics , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Models, Molecular , Point Mutation , Quinolones/pharmacokineticsABSTRACT
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Line , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Pyrrolidinones/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrrolidinones/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Enzyme Inhibitors/chemistry , Humans , Pyrrolidinones/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
