Finding the Achilles heel(s) of triple negative breast cancer

Breast cancer is the most prevalent and lethal cancer in women. 15% of breast cancers do not overexpress the estrogen, progesterone or HER2 receptors also known as Triple Negative Breast Cancers (TNBC). This type of cancers is more aggressive, has poor prognosis, and lack any targeted therapy. This stems partly from our lack of understanding of driver events in TNBC and for lack of validated targets for its pathogenicity. We propose to identify new molecular drivers of TNBC and their respective pathways via covalent fragment phenotypic screening, utilizing an innovative electrophilic fragment library. We have assembled a collection of 993 electrophilic fragments for cellular phenotypic screening that will be used to discover proteins that selectively contribute to TNBC viability, validate them orthogonally via knockdowns and explore their biological roles in TNBC pathogenicity. We will harness the covalent nature of these compounds to pull down their target proteins and characterize them via proteomics. This library can offer an unprecedented window to the working of TNBCs.