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

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 IC 50 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/VEGF 165 interaction assay platform. Analogues 4e and 4f significantly reduced the interaction between CRYAB/VEGF 165 , 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.

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

“…However, overexpression of Hsp27 leading to cardiomyopathy or protecting myocardium is controversial [95,[97][98][99][100][101]. (2) CryAB protects against caspase-3 activation and Bcl-2 [113] and maintains mitochondrial function [112]. CryAB R120G leads to cardiomyopathies via reductive stress [116,117].…”

“…Protection by CryAB overexpression is connected with maintenance of appropriate mitochondrial protein levels, inhibition of aberrant mitochondrial permeability transition pore activation, and mitochondrial membrane potential (Δ Ψ ) [112]. Moreover, CryAB brings protection against apoptosis through inhibiting caspase-3 activation, segregation of the antiapoptotic protein Bcl-2, and prevention of Bcl-2 translocation into the mitochondria [113]. In addition, CryAB is also inducible in response to other forms of stress such as inflammation and heat [114].…”