ABSTRACT
DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 µM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Amino Acid Sequence , Antineoplastic Agents/chemical synthesis , Catalytic Domain , Models, Molecular , Molecular Sequence Data , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/chemistry , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacology , Structure-Activity Relationship , Substrate Specificity , Sulfones/chemistryABSTRACT
INTRODUCTION: Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis. METHODS: VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP). RESULTS: VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected. CONCLUSIONS: Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
Subject(s)
Caspases/drug effects , Enzyme Inhibitors/pharmacology , Shock, Septic/drug therapy , Animals , Apoptosis/drug effects , Apoptosis/immunology , Caspase Inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/immunology , Enzyme Inhibitors/therapeutic use , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/blood , Lipopolysaccharides/pharmacology , Male , Mice , Models, Animal , Rats , Rats, Sprague-Dawley , Shock, Septic/physiopathology , Survival , Treatment OutcomeABSTRACT
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.
Subject(s)
Piperazines/chemistry , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Aurora Kinases , Cell Line, Tumor , Computer Simulation , Crystallography, X-Ray , Drug Design , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Mutant Proteins/antagonists & inhibitors , Mutant Proteins/metabolism , Piperazines/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Structure-Activity RelationshipSubject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Aurora Kinases , Humans , Mitosis/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/metabolismABSTRACT
A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Benzamides/chemical synthesis , Interleukin-1beta/antagonists & inhibitors , Purinergic P2 Receptor Antagonists , Adamantane/pharmacology , Animals , Benzamides/pharmacology , Blood Proteins/metabolism , Crystallography, X-Ray , Humans , In Vitro Techniques , Molecular Conformation , Monocytes/metabolism , Protein Binding , Rats , Receptors, Purinergic P2X7 , Structure-Activity RelationshipABSTRACT
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Subject(s)
Adenosine Triphosphate/therapeutic use , Adenosine/analogs & derivatives , Membrane Proteins/antagonists & inhibitors , Purinergic P2 Receptor Antagonists , Thrombosis/prevention & control , Adenosine/therapeutic use , Administration, Oral , Animals , Humans , Receptors, Purinergic P2Y12 , TicagrelorABSTRACT
In this millennium, global drylands face a myriad of problems that present tough research, management, and policy challenges. Recent advances in dryland development, however, together with the integrative approaches of global change and sustainability science, suggest that concerns about land degradation, poverty, safeguarding biodiversity, and protecting the culture of 2.5 billion people can be confronted with renewed optimism. We review recent lessons about the functioning of dryland ecosystems and the livelihood systems of their human residents and introduce a new synthetic framework, the Drylands Development Paradigm (DDP). The DDP, supported by a growing and well-documented set of tools for policy and management action, helps navigate the inherent complexity of desertification and dryland development, identifying and synthesizing those factors important to research, management, and policy communities.
