Discovery of a novel non-toxic analog of clofarabine for the treatment of triple-negative breast cancer.

Breast cancer is the second most prevalent cancer in the world. Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer accounts for 15-20 % of all diagnosed breast cancer cases. Chemotherapy is standard of care for TNBC patients with metastatic disease and poly (ADP-ribose) polymerase inhibitors are approved in patients with BRCA1/2 mutations. Despite initial response, clinical resistance rapidly develops, and few options exist as later-line treatments. Therefore, new targeted approaches are urgently needed to treat TNBC. Clofarabine, a purine nucleoside analog developed at Southern Research, is an FDA-approved treatment for relapsed or refractory pediatric acute lymphoblastic leukemia but has lower therapeutic index when tested against TNBC cells in vitro due to its significant cytotoxicity against normal mammary epithelial cells. Our preliminary structure-activity relationship study resulted in the identification of analog 9 with enhanced activity against TNBC cells and improved cytotoxicity. One major advantage of analog 9 is that a pilot dose range finding study demonstrated that this analog elicited no signs of toxicity, whereas clofarabine was not well tolerated.