@article{Neumann-Mufweba_Kimani_Khan_Chibale_Prince_2022, title={The diaryl-imidazopyridazine anti-plasmodial compound, MMV652103, exhibits anti-breast cancer activity}, volume={21}, url={https://www.excli.de/index.php/excli/article/view/4323}, DOI={10.17179/excli2021-4323}, abstractNote={<p class="Abstract"><span lang="EN-US">Breast cancer is the most common malignancy in women worldwide and it remains a global health burden, in part, due to poor response and tolerance to current therapeutics. Drug r<span style="color: black;">epurposing, which seeks to </span>identify new indications for existing and investigational drugs,<span style="color: black;"> has become an exciting strategy to address these challenges</span>. Here we describe the anti-breast cancer activity of a <span style="color: black;">diaryl-imidazopyridazine compound, <a name="_Hlk81473567"></a>MMV652103, which was previously identified for its anti-plasmodial activity. We demonstrate that MMV652103 potently inhibits the oncogenic PI4KB and PIK3C2G lipid kinases, is selectively cytotoxic to MCF7 and T47D estrogen receptor positive breast cancer cells and inhibits their ability to survive and migrate. The underlying mechanisms involved included the induction of reactive oxygen species and activation of the DNA damage and p38 MAPK stress signaling pathways. This was associated with a G1 cell cycle arrest and an increase in levels of the cyclin-dependent kinase inhibitor p21 and activation of apoptotic and autophagic cell death pathways. Lastly, MMV652103 significantly reduced the weight and metastases of MCF7 induced tumors in an <em>in vivo</em> chick embryo model and displayed a favorable safety profile. These findings position MMV652103 as a promising chemotherapeutic in the treatment of oestrogen receptor positive breast cancers.</span></span></p>}, journal={EXCLI Journal}, author={Neumann-Mufweba, Alexis and Kimani, Serah and Khan, Saif Feroz and Chibale, Kelly and Prince, Sharon}, year={2022}, month={Apr.}, pages={656–679} }