Apoptosis Targeting Therapeutics in Clinical Trials

Apoptosis (called as programmed cell death) is vital for maintaining homeostatic balance between cell survival/cell deaths in metazoan cells. Apoptosis is regulated through extrinsic (or receptor mediated) and intrinsic (or mitochondria mediated) pathways. The pro-apoptotic proteins (e.g. Bax, Bak, Bad, Bcl-Xs, Bid, Bik, Bim and Hrk) and the anti-apoptotic proteins (e.g. Bcl-2, Bcl-XL, Bcl-W, Bfl-1 and Mcl-1) are crucial to control the apoptotic pathways. Dysfunctions of apoptosis pathways are implicated in cancer as defects in these pathways not only promote tumorigenesis but also confer resistance to cancer cells to most conventional chemotherapies as well as radiotherapy. The apoptosis occurs by imbalanced proapoptotic and anti-apoptotic protein levels, impaired or reduced death receptor signalling and caspase function. Hence, targeting apoptosis pathways is considered as an attractive strategy for therapeutic intervention in cancer. The past decade recorded tremendous advances in this area especially small molecular intervention of apoptosis pathways for cancer treatment which resulted in several compounds under clinical development. This chapter reviews the current progressions in the development of bioactive molecules targeting apoptotic pathways with special emphasis on small molecular anticancer drugs under clinical trials. Some excellent examples are; nutlins, MI-888, MI-219 and SM-164 which target MDM2, ABT-263, AT-406 and GX15- 070MS which target Bcl-2 family of proteins, birinapant, GDC-0917, HGS-1029 and LCL-161 which target IAPs (inhibitors of apoptotic proteins). The content of this chapter will be enlightening the readers in academic and research to update their knowledge on the anticancer drugs especially target proteins responsible for apoptosis.

Keywords: Apoptosis, BCL family proteins, Cancer, Caspase, Clinical trials, IAP, MDM2, Nutlins, p53, Pro-apoptotic protein.