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Title: Design, synthesis and biological evaluation of small-molecules targeting the Mdmx-p53 interaction and the Atad2 bromodomain for cancer therapy
Author: Adhikari, Santosh
ISNI:       0000 0004 6423 6856
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2016
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In this thesis small molecule inhibitors of MDMX-p53 interaction, and ATAD2 bromodomain are investigated. In many human cancers, the function of the tumour suppressor protein p53 is inhibited by the overexpression of MDM2 or MDMX. Modulation of MDM2-p53 and MDMX-p53 interactions is therefore an attractive strategy for anticancer drug discovery. A number of small molecule inhibitors of the MDM2-p53 interaction have been reported to date and several have entered clinical trials. Although MDM2 and MDMX have a high sequence homology, most of the small molecule MDM2 inhibitors show significantly lower binding affinity towards MDMX. A series of 2,4-aminothiazoles including compound 1 with modest inhibitory activity against the MDM2-p53 and MDMX-p53 interactions has been reported. The series was extended to a pyrrole series, which led to the discovery of compound 2 with low micromolar dual inhibition of MDM2/MDMX and structure-activity relationship studies were conducted. An ELISA was used to examine potency against MDM2-p53 and MDMX-p53. Although, the assay gave results in agreement with literature values for some inhibitors of the MDM2-p53 interaction, the potencies of the published dual inhibitors RO-2443 3 and RO-5963 4 were around 1000-fold lower than reported. Therefore, an HTRF assay was developed, which provided IC50 values comparable to the reported values for inhibition of MDM2-p53 and MDMX-p53 by RO-5963. Co-crystallisation experiments, using three different constructs of MDMX, were attempted using 15 compounds. vi Bromodomains are protein modules that function as epigenetic readers of histone lysine acetylation. ATAD2, a bromodomain containing protein, is overexpressed in a wide range of human cancers including breast, lung, prostate, ovarian, liver, osteosarcoma and gastrointestinal carcinomas. Due to the polar and flexible nature of the binding surface, ATAD2 has been considered as a challenging target for ligand discovery. Therefore, very few potent and selective inhibitors of ATAD2 bromodomains have been reported to date. Extensive SAR studies around hit 5 obtained from a fragment screening led to the identification of a sub-millimolar inhibitor 6 of ATAD2 bromodomain. Co-crystal structures of ATAD2 were used to guide compound design and synthesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available