ABSTRACT
Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients. Genomic profiling of tumors refractory to current FGFR inhibitors in the clinic has revealed several acquired driver alterations that could be the target of next generation therapeutics. Herein, we describe how structure-based drug design (SBDD) was used to enable the discovery of the potent and kinome selective pan-FGFR inhibitor KIN-3248, which is active against many acquired resistance mutations. KIN-3248 is currently in phase I clinical development for the treatment of advanced tumors harboring FGFR2 and/or FGFR3 gene alterations.
Subject(s)
Neoplasms , Receptor, Fibroblast Growth Factor, Type 2 , Humans , Receptor, Fibroblast Growth Factor, Type 2/genetics , Neoplasms/drug therapy , Neoplasms/genetics , Mutation , Disease Progression , Protein Kinase Inhibitors/adverse effects , Receptor, Fibroblast Growth Factor, Type 3ABSTRACT
RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS). However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.
Subject(s)
Melanoma , Proto-Oncogene Proteins B-raf , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Cell Line, Tumor , Melanoma/pathology , MAP Kinase Signaling System , MutationABSTRACT
Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).
Subject(s)
Enzyme Inhibitors/pharmacology , Histone Demethylases/antagonists & inhibitors , Organic Chemicals/pharmacology , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Humans , Organic Chemicals/chemistry , Structure-Activity RelationshipABSTRACT
The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.
Subject(s)
Drug Design , Isoquinolines/chemistry , Nuclear Proteins/antagonists & inhibitors , Transcription Factors/antagonists & inhibitors , Binding Sites , Cell Cycle Proteins , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Molecular Dynamics Simulation , Nuclear Proteins/metabolism , Protein Structure, Tertiary , Structure-Activity Relationship , Transcription Factors/metabolismABSTRACT
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies.
Subject(s)
Azepines/chemistry , Azepines/pharmacology , Cell Cycle Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , 4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacokinetics , 4-Aminobenzoic Acid/pharmacology , Administration, Oral , Adult , Azepines/pharmacokinetics , Cell Line, Tumor , Drug Discovery , Humans , Protein Kinase Inhibitors/pharmacokinetics , Young Adult , Polo-Like Kinase 1ABSTRACT
The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Pyrimidinones/chemical synthesis , Animals , Binding Sites , Biological Availability , Crystallography, X-Ray , Cytochrome P-450 Enzyme Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dogs , Macaca fascicularis , Models, Molecular , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.
Subject(s)
Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemic Agents/chemical synthesis , Piperidines/chemical synthesis , Pyrimidinones/chemical synthesis , Quinazolinones/chemical synthesis , Uracil/analogs & derivatives , Animals , Binding Sites , Blood Glucose/analysis , Cytochrome P-450 Enzyme Inhibitors , Diabetes Mellitus, Experimental/drug therapy , Dogs , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/drug effects , Female , Glucose Tolerance Test , Haplorhini , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrimidinones/pharmacokinetics , Pyrimidinones/pharmacology , Quinazolinones/pharmacokinetics , Quinazolinones/pharmacology , Rats , Rats, Wistar , Structure-Activity Relationship , Uracil/chemical synthesis , Uracil/pharmacokinetics , Uracil/pharmacologyABSTRACT
The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.
