ABSTRACT
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
A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.
Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/chemistry , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Female , Half-Life , Humans , Hydrogen-Ion Concentration , Mice , Mice, Nude , Mutation , Neoplasms/drug therapy , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/metabolism , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.
