Reference Detail

Ref Type

Journal Article

PMID

(24278380)

Authors

Wei SJ, Joseph T, Chee S, Li L, Yurlova L, Zolghadr K, Brown C, Lane D, Verma C, Ghadessy F

Title

Inhibition of nutlin-resistant HDM2 mutants by stapled peptides.

Journal	Vol	Issue	Date	Pages	Journal Short Title
PloS one	8	11	2013	e81068	PLoS One

URL

Abstract Text

Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, and display reduced discrimination between the wild-type and mutant HDM2s with regards to functional abrogation of interaction with p53. The larger interaction footprint afforded by stapled peptides suggests that this class of ligands may prove comparatively more resilient to acquired resistance in a clinical setting.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
MDM2	M62A	missense	unknown	MDM2 M62A lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). M62A has been shown to confer MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 25115702, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023).	Y
MDM2	P20L	missense	unknown	MDM2 P20L lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). P20L has been shown to confer moderate MDM2 inhibitor resistance in cell culture (PMID: 23653682, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023).	Y
MDM2	Q24R	missense	unknown	MDM2 Q24R lies within the TP53-binding domain of the Mdm2 protein (PMID: 14707282). Q24R has been shown to confer MDM2 inhibitor resistance in culture (PMID: 23653682, PMID: 24278380), but has not been biochemically characterized and therefore, its effect on Mdm2 protein function is unknown (PubMed, Nov 2023).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MDM2 Q24R	Advanced Solid Tumor	predicted - resistant	Nutlin-3a	Preclinical - Biochemical	Actionable	In a preclinical study, MDM2 Q24R conferred resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in a reporter assay and decreased inhibition of the Mdm2-Tp53 interaction in culture (PMID: 24278380).	24278380
MDM2 M62A	Advanced Solid Tumor	predicted - resistant	Nutlin-3a	Preclinical - Biochemical	Actionable	In a preclinical study, MDM2 M62A conferred resistance to Nutlin-3a as demonstrated by decreased restoration of Tp53 activity in a reporter assay and decreased inhibition of the Mdm2-Tp53 interaction in culture (PMID: 24278380).	24278380