
IndraLab
Statements
sparser
"To engineer the cyclotide MCoTI-I for antagonizing protein-protein interactions between p53 and Hdm2 or HdmX we used the phage-selected α-helical peptide PMI ( xref ). xref This peptide conserves the residues Phe19, Trp23 and Leu26 of p53 required for the interaction with Hdm2 and HdmX, and is able to bind the p53 binding domains of Hdm2 and Hdmx with low nM affinity. xref The PMI peptide was grafted onto the cyclotide scaffold using loop 6."
sparser
"In conclusion, this research describes the implementation of the high-throughput conditional transcription system to profile the functional elements important for the antagonism of Hdm2–p53 and Hdmx–p53 interactions, implicated as causative events in a large proportion of human malignancies."
sparser
"There is great interest in molecules that inhibit interactions between p53 and its negative regulators hDM2 and hDMX, as these molecules have validated potential against cancers that overexpress one or both of these oncoproteins. xref , xref We reported that substituted β 3 -peptides can inhibit these interactions xref , xref and, more recently, that minimally cationic β 3 -peptides are sufficiently cell permeable to upregulate p53-dependent genes in live cells. xref , xref These observations, coupled with the established intracellular stability of β-peptides xref – xref and the recently reported structures of hDM2 xref and hDMX, xref motivated us to exploit computational methods to identify β-peptides with improved potency and/or selectivity."
sparser
"Given that both Hdm2 and HdmX bind to the transactivation domain of p53, targeting both p53-binding domains has been shown to be critical for the activation of the p53 tumor suppressor in cancer cells overexpressing Hdm2 and/or HdmX. xref In agreement with this, the cyclotide MCo-PMI was able to reactivate the p53 tumor suppressor pathway in different cancer lines expressing different levels of Hdm2 and/or HdmX and was not cytotoxic to non-cancer cells or cancer cells with disfunctional p53."
sparser
"Compounds broadly classified as chalcones have been shown to exhibit anticancer activity through multiple mechanisms, including disruption of p53 interactions with MDM2 or HDM2, xref , xref inhibition of p-glycoprotein, xref – xref and disruption of microtubule polymerization. xref – xref Many of the latter compounds were designed as analogs of colchicine and combretastatins, natural products known to bind β-tubulin."