Triple-negative breast cancer (TNBC) is a subtype of poor prognosis, highly invasive and difficult-to-treat breast cancers accounting for approximately 15% of clinical cases. Given the poor outlook and lack of sustained response to conventional therapies, TNBC has been the subject of intense studies on new therapeutic approaches in recent years. The development of targeted cancer therapies, often in combination with established chemotherapy, has been applied to a number of new clinical studies in this setting in recent years. This review will highlight recent therapeutic advances in TNBC, focusing on small-molecule drugs and their associated biological mechanisms of action, and offering the possibility of improved prospects for this patient group in the near future.

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.