Triple-negative breast cancer (TNBC) represents one of the most difficult cancers to treat and there is currently no targeted therapeutics which are FDA approved. TNBC is found in 15-30% of all breast cancers. Kinases are a family of proteins that have been demonstrated to be important targets in cancer and are currently the focus of up to 25% of all drugs in development. p38 mitogen-activated protein kinases (p38 MAPKs) are a class of mitogen-activated protein kinases and cellular Src kinase (c-Src) is a non-receptor tyrosine kinase protein that independently have been demonstrated to be important targets in various cancers. While inhibitors of c-Src have been developed they show little efficacy in TNBC. However all current FDA-approved inhibitors of c-Src act by binding the active conformation of the kinase.
Novel dual inhibitors for c-Src/p38 MAP kinase
Novel inhibitors targeting c-Src in an inactive conformation (termed DFG-out) have improved efficacy against TNBCs. A new compound was developed to inhibit c-Src and also demonstrates potent binding to the p38 family of MAPKs. In mouse xenograft models of TNBC, treatment with this compound resulted in a decrease in tumor growth. These results promote the p38 family kinases as an attractive target in TNBC and dual c-Src/p38 kinase inhibition as a promising strategy for developing a targeted therapeutic for TNBC.
- triple-negative breast cancer
- other solid tumors
- no approved compounds for TNBC
- dual c-Src/p38 inhibitor
- low in vivo toxicity
- potent activity in vivo
- good in vivo pharmacokinetics