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Fragment growing to retain or alter the selectivity of anchored kinase hinge-binding fragments
(ROYAL SOC CHEMISTRY, 2014-01-01)
<p>The selectivity patterns of kinase hinge-binding fragments can be retained during fragment growing, suggesting a new way to control poly-pharmacology.</p>
Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
(AMER CHEMICAL SOC, 2016-06-09)
Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy ...
Exploiting Protein Conformational Change to Optimize Adenosine-Derived Inhibitors of HSP70.
(AMER CHEMICAL SOC, 2016-05-26)
HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought ...
Labelled chemical probes for demonstrating direct target engagement in living systems.
(FUTURE SCI LTD, 2019-05-24)
Demonstrating target engagement in living systems can help drive successful drug discovery. Target engagement and occupancy studies in cells confirm direct binding of a ligand to its intended target protein and provide the ...
A critical evaluation of the approaches to targeted protein degradation for drug discovery.
(Elsevier BV, 2019-04-03)
There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional ...
Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-Endoribonuclease.
(AMER CHEMICAL SOC, 2019-02-19)
A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component ...
Solution NMR assignment of the ARC4 domain of human tankyrase 2.
(SPRINGER, 2019-04-15)
Tankyrases are poly(ADP-ribose)polymerases (PARPs) which recognize their substrates via their ankyrin repeat cluster (ARC) domains. The human tankyrases (TNKS/TNKS2) contain five ARCs in their extensive N-terminal region; ...
Metabolomic changes of the multi (-AGC-) kinase inhibitor AT13148 in cells, mice and patients are associated with NOS regulation.
(SPRINGER, 2020-04-13)
INTRODUCTION: To generate biomarkers of target engagement or predictive response for multi-target drugs is challenging. One such compound is the multi-AGC kinase inhibitor AT13148. Metabolic signatures of selective signal ...
Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
(NATURE PUBLISHING GROUP, 2019-12-13)
The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in ...
A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines
(PERGAMON-ELSEVIER SCIENCE LTD, 2018-01-17)
The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp3-enriched azacycles was investigated. In the current study, we have identified whether a pKa-dependent Mitsunobu cyclodehydration or a pKa-independent ...