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The discovery of purine-based agents targeting triple-negative breast cancer and the αB-crystallin/VEGF protein-protein interaction

Fosu-Mensah, Nelly A., Jiang, Wen, Brancale, Andrea, Cai, Jun and Westwell, Andrew D. 2019. The discovery of purine-based agents targeting triple-negative breast cancer and the αB-crystallin/VEGF protein-protein interaction. Medicinal Chemistry Research 28 (2) , pp. 182-202. 10.1007/s00044-018-2275-9

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Abstract

Oestrogen receptor-negative breast cancer, particularly subtypes such as triple-negative breast cancer (TNBC, around 10–15% of cases), are characterised by poor long-term survival, poor response to therapy and early progression to metastasis. Purine-based compounds represent a privileged scaffold in anticancer drug design, with several clinically approved and experimental agents in clinical development comprising a purine core structure. In this study, a series of new purine-based compounds were synthesised; seven of the new analogues were found to significantly reduce the in vitro viability of TNBC cell lines (MDA-MB-231 and MDA-MB-436) with IC50 values of ≤50 μM. In previous work, we have proposed a new concept for targeting angiogenesis driving TNBC progression, by disrupting the protein–protein interaction between the molecular chaperone αB-crystallin (CRYAB) and VEGF. Since previous clinical studies applying anti-VEGF therapy to TNBC patients have met with limited success, we were interested to test our most promising purine analogues against CRYAB/VEGF, using a custom-designed cell-based CRYAB/VEGF165 interaction assay platform. Analogues 4e and 4f significantly reduced the interaction between CRYAB/VEGF165, and compound 4e (100 μM) was also found to decrease the levels of soluble VEGF expressed by MDA-MB-231 cells by 40%. In conclusion, these promising early activity profiles warrant further investigation to validate this concept.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer Verlag (Germany)
ISSN: 1054-2523
Funders: Cancer Research Wales
Date of First Compliant Deposit: 3 January 2019
Date of Acceptance: 8 December 2018
Last Modified: 28 Jun 2019 03:02
URI: http://orca.cf.ac.uk/id/eprint/117950

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