Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines
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چکیده
منابع مشابه
Harnessing Fluorine–Sulfur Contacts and Multipolar Interactions for the Design of p53 Mutant Y220C Rescue Drugs
Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 μM, thereby increasing the melting tempe...
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p53, as a transcription factor, plays an eminent role in tumor suppression. Y220C, a substitution mutation, which cause major structural changes in the protein, is evidenced to form a new protein cavity. This cavity is reckoned to accommodate small drug candidates, which may play a key role in cancer suppression. In the present, study we have tried to determine a drug candidate based on structu...
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Soluble proteins must protect their structural integrity from water attack by wrapping interactions which imply the clustering of nonpolar residues around the backbone hydrogen bonds. Thus, poorly wrapped hydrogen bonds constitute defects which have been identified as promoters of protein associations since they favor the removal of hydrating molecules. More specifically, a recent study of our ...
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The destabilizing p53 cancer mutation Y220C creates a druggable surface crevice. We developed a strategy exploiting halogen bonding for lead discovery to stabilize the mutant with small molecules. We designed halogen-enriched fragment libraries (HEFLibs) as starting points to complement classical approaches. From screening of HEFLibs and subsequent structure-guided design, we developed substitu...
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Mutations of the tumor protein p53 gene, a tumor suppressor, are one of the most frequent genetic alterations observed in cancer. It has been reported that mutations in p53 result in the loss of wild-type p53 activity, and the gain of novel oncogenic properties that promote tumor growth and progression. Recent studies have demonstrated that a number of microRNAs (miRs) are involved in the post-...
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ژورنال
عنوان ژورنال: European Journal of Medicinal Chemistry
سال: 2018
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2018.04.035