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AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
TLDR
Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damage agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings. Expand
Death by releasing the breaks: CHK1 inhibitors as cancer therapeutics.
TLDR
Recent advances and controversies in the development and application of CHK1 inhibitors as cancer therapeutics are summarized. Expand
Flipped out: structure-guided design of selective pyrazolylpyrrole ERK inhibitors.
TLDR
A novel series of pyrazolylpyrroles are identified as inhibitors of ERK, and structure-guided optimization culminated in the discovery of 6p, a potent and selective inhibitor ofERK. Expand
Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control.
TLDR
Discovery of a conformational change for lead compound 2, when bound to ERK2 relative to antitarget GSK3, enabled structure-guided selectivity optimization, which led to the discovery of 11e, a potent, selective, and orally bioavailable inhibitor of ERK. Expand
Treatment and Prevention of Urinary Tract Infection with Orally Active FimH Inhibitors
TLDR
Small–molecular weight compounds termed mannosides that specifically inhibit the FimH type 1 pilus lectin of UPEC, which mediates bacterial colonization, invasion, and formation of recalcitrant intracellular bacterial communities in the bladder epithelium, promise to provide substantial benefit to women suffering from chronic and recurrent urinary tract infections. Expand
Structure-based drug design and optimization of mannoside bacterial FimH antagonists.
TLDR
Dimeric analogues linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. Expand
MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A
TLDR
A mitofusin agonist normalized axonal mitochondrial trafficking within sciatic nerves of MFN2 Thr105→Met105 mice, promising a therapeutic approach for CMT2A and other untreatable diseases of impaired neuronal mitochondrial dynamism and/or trafficking. Expand
Inhibitors of checkpoint kinases: from discovery to the clinic.
TLDR
This review focuses on advances reported both in the literature and at conferences from 2005 to date concerning the chemical design and optimization of checkpoint kinase inhibitors for the treatment of cancer. Expand
Discovery of checkpoint kinase inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by structure-based design and optimization of thiophenecarboxamide ureas.
TLDR
The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Expand
Antivirulence C-Mannosides as Antibiotic-Sparing, Oral Therapeutics for Urinary Tract Infections
TLDR
It is found that FimH binding is stereospecifically modulated by hydroxyl substitution on the methylene linker, where the R-hydroxy isomer has a 60-fold increase in potency. Expand
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