ABSTRACT
Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.
Subject(s)
Membrane Proteins/agonists , Nucleotides, Cyclic/chemistry , Pyrimidines/chemistry , Administration, Intravenous , Animals , Binding Sites , Cell Line, Tumor , Half-Life , Humans , Immunotherapy , Membrane Proteins/metabolism , Mice , Molecular Docking Simulation , Neoplasms/pathology , Neoplasms/therapy , Nucleotides, Cyclic/metabolism , Nucleotides, Cyclic/therapeutic use , Phosphates/chemistry , Rats , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzazepines/chemical synthesis , Cell Cycle Proteins/antagonists & inhibitors , Lactams/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Thiones/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Benzazepines/pharmacokinetics , Benzazepines/pharmacology , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Mice , Mice, Nude , Mitosis , Models, Molecular , Neoplasm Transplantation , Protein Conformation , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiones/pharmacokinetics , Thiones/pharmacology , Transplantation, Heterologous , Polo-Like Kinase 1ABSTRACT
Inhibitors of IkappaB kinase (IKK) have long been sought as specific regulators of NF-kappaB. A screening effort of the endogenous IKK complex allowed us to identify 5-bromo-6-methoxy-beta-carboline as a nonspecific IKK inhibitor. Optimization of this beta-carboline natural product derivative resulted in a novel class of selective IKK inhibitors with IC(50)s in the nanomolar range. In addition, we show that one of these beta-carboline analogues inhibits the phosphorylation of IkappaBalpha and subsequent activation of NF-kappaB in whole cells, as well as blocking TNF-alpha release in LPS-challenged mice.
