14-3-3σ and Its Modulators in Cancer

14-3-3 sigma is an acidic homodimer protein with more than one hundred different protein partners associated with oncogenic signaling and cell cycle regulation. This review aims to highlight the crucial role of 14-3-3 sigma in controlling tumor growth and apoptosis and provide a detailed discussion on the structure-activity relationship and binding interactions of the most recent 14-3-3 sigma protein-protein interaction (PPI) modulators reported to date, which has not been reviewed previously. This includes the new fusicoccanes stabilizers (FC-NAc, DP-005), fragment stabilizers (TCF521-123, TCF521-129, AZ-003, AZ-008), phosphate-based inhibitors (IMP, PLP), peptide inhibitors (2a-d), as well as inhibitors from natural sources (85531185, 95911592). Additionally, this review will also include the discussions of the recent efforts by a different group of researchers for understanding the binding mechanisms of existing 14-3-3 sigma PPI modulators. The strategies and state-of-the-art techniques applied by various group of researchers in the discovery of a different chemical class of 14-3-3 sigma modulators for cancer are also briefly discussed in this review, which can be used as a guide in the development of new 14-3-3 sigma modulators in the near future.