ABSTRACT
A novel family of potent dual inhibitors of CK2 and the Pim kinases was discovered by modifying the scaffolds of tricyclic Pim inhibitors. Several analogs were active at single digit nanomolar IC(50) values against CK2 and the Pim isoforms Pim-1 and Pim-2. The molecules displayed antiproliferative activity in various cell phenotypes in the low micromolar and submicromolar range, providing an excellent starting point for further drug discovery optimization.
Subject(s)
Antineoplastic Agents/pharmacology , Casein Kinase II/antagonists & inhibitors , Cell Proliferation/drug effects , Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Cell Line, Tumor , Drug Discovery , Humans , Inhibitory Concentration 50 , Neoplasms/drug therapyABSTRACT
Protein kinase CK2 is a potential drug target for many diseases including cancer and inflammation disorders. The crystal structure of clinical candidate CX-4945 1 with CK2 revealed an indirect interaction with the protein through hydrogen bonding between the NH of the 3-chlorophenyl amine and a water molecule. Herein, we investigate the relevance of this hydrogen bond by preparing several novel tricyclic derivatives lacking a NH moiety at the same position. This SAR study allowed the discovery of highly potent CK2 inhibitors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Casein Kinase II/antagonists & inhibitors , Quinolines/chemistry , Casein Kinase II/chemistry , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Protein Conformation , Quinolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Naphthyridines/chemistry , Naphthyridines/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Leukemia/drug therapy , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Pyrroles/chemical synthesis , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Acenaphthenes , Adrenocorticotropic Hormone/antagonists & inhibitors , Animals , Biological Availability , Blood-Brain Barrier/metabolism , Cells, Cultured , Cyclic AMP/biosynthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , In Vitro Techniques , Male , Mice , Pituitary Gland/cytology , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Corticotropin-Releasing Hormone/metabolism , Stress, Psychological/metabolism , Structure-Activity RelationshipABSTRACT
SAR studies of 1,3,5-triazine-2,4,6-triones as human gonadotropin-releasing hormone receptor antagonists resulted in potent compounds. The best compound from the series had a binding affinity of 2 nM.