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
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Glycine/analogs & derivatives , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombin III/chemistry , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
A novel isonitrile derivative was synthesized and used in an Ugi four component coupling reaction to explore aryl group substitution effects on inhibition of the coagulation cascade serine protease factor Xa.
Subject(s)
Factor Xa Inhibitors , Glycine/analogs & derivatives , Glycine/chemical synthesis , Glycine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Indicators and Reagents , Structure-Activity RelationshipABSTRACT
A generalized Kuramoto model of coupled phase oscillators with a slow varying coupling matrix is studied. The dynamics of the coupling coefficients is driven by the phase difference of pairs of oscillators in such a way that the coupling strengthens for synchronized oscillators and weakens for nonsynchronized pairs. The system possesses a family of stable solutions corresponding to synchronized clusters of different sizes. A particular cluster can be formed by applying external driving at a given frequency to a group of oscillators. Once established, the synchronized state is robust against noise and small variations in natural frequencies. The phase differences between oscillators within the synchronized cluster can be used for information storage and retrieval.
Subject(s)
Learning , Neural Networks, Computer , Neuronal Plasticity , Oscillometry , Artificial Intelligence , Information Storage and Retrieval , Learning/physiology , Memory/physiology , Models, Neurological , Nerve Net/physiology , Neuronal Plasticity/physiology , Synapses/physiologyABSTRACT
In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.
