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
A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aß1-40 at 60 mg/kg (PO).
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Chromans/chemical synthesis , Protease Inhibitors/chemical synthesis , Spiro Compounds/chemical synthesis , Animals , Brain/metabolism , Cathepsin D , Chromans/pharmacokinetics , Chromans/pharmacology , HEK293 Cells , Humans , Inhibitory Concentration 50 , Male , Mice , Models, Molecular , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Herein we describe the discovery of a novel series of ATP competitive B-Raf inhibitors via structure based drug design (SBDD). These pyridopyrimidin-7-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies.
Subject(s)
Drug Discovery , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrimidinones/pharmacology , Administration, Oral , Biological Availability , Crystallography, X-Ray , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidinones/chemistry , Pyrimidinones/pharmacokineticsABSTRACT
Herein we describe a novel series of ATP competitive B-Raf inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 17, a potent, selective and orally available agent with improved physicochemical and pharmacokinetic properties.
Subject(s)
Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Animals , Chemistry, Physical , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Mice , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure-activity relationships around a novel series of B-Raf(V600E) inhibitors are reported. The enzymatic and cellular potencies of inhibitors derived from two related hinge-binding groups were compared and3-methoxypyrazolopyridine proved to be superior. The 3-alkoxy group of lead B-Raf(V600E) inhibitor 1 was extended and minimally affected potency. The propyl sulfonamide tail of compound 1, which occupies the small lipophilic pocket formed by an outward shift of the αC-helix, was expanded to a series of arylsulfonamides. X-ray crystallography revealed that this lipophilic pocket unexpectedly enlarges to accommodate the bulkier aryl group.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/pharmacology , Pyridines/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The V600E mutation of B-Raf kinase results in constitutive activation of the MAPK signaling pathway and is present in approximately 7% of all cancers. Using structure-based design, a novel series of pyrazolopyridine inhibitors of B-Raf(V600E) was developed. Optimization led to the identification of 3-methoxy pyrazolopyridines 17 and 19, potent, selective, and orally bioavailable agents that inhibited tumor growth in a mouse xenograft model driven by B-Raf(V600E) with no effect on body weight. On the basis of their in vivo efficacy and preliminary safety profiles, 17 and 19 were selected for further preclinical evaluation.
ABSTRACT
Herein we describe a novel pyrazole-based class of ATP competitive B-Raf inhibitors. These inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. A subset of these inhibitors has demonstrated the ability to inhibit downstream ERK phosphorylation in LOX tumors from mouse xenograft studies.
