24455-93-4Relevant articles and documents
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
Brough, Paul A.,Baker, Lisa,Bedford, Simon,Brown, Kirsten,Chavda, Seema,Chell, Victoria,D’Alessandro, Jalanie,Davies, Nicholas G. M.,Davis, Ben,Le Strat, Loic,Macias, Alba T.,Maddox, Daniel,Mahon, Patrick C.,Massey, Andrew J.,Matassova, Natalia,McKenna, Sean,Meissner, Johannes W. G.,Moore, Jonathan D.,Murray, James B.,Northfield, Christopher J.,Parry, Charles,Parsons, Rachel,Roughley, Stephen D.,Shaw, Terry,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Stefaniak, Emma,Robertson, Alan,Wang, Yikang,Webb, Paul,Whitehead, Neil,Wood, Mike
supporting information, p. 2271 - 2286 (2017/04/03)
Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors
Yin, Yan,Zheng, Ke,Eid, Nibal,Howard, Shannon,Jeong, Ji-Hak,Yi, Fei,Guo, Jia,Park, Chul Min,Bibian, Mathieu,Wu, Weilin,Hernandez, Pamela,Park, Hajeung,Wu, Yuntao,Luo, Jun-Li,Lograsso, Philip V.,Feng, Yangbo
, p. 1846 - 1861 (2015/04/21)
The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
HYDROGEN PEROXIDE SENSORS BASED UPON PHOTO-INDUCED ELECTRON TRANSFER
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, (2011/02/24)
The invention provides compounds of formula I F-L-Q (I) where F comprises a fluorophore capable of absorbing energy at an excitation wavelength and, in the absence of a quencher, emitting energy at an emission wavelength, which is different than the excit
