Abstract 3551: Discovery of orally bioavailable novel Mcl-1 inhibitors that exhibit selective anti-proliferative activity in Mcl-1 sensitive cancer cell lines

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 familyof proteins that regulate apoptosis. Amplification of Mcl-1 is found in various cancers, which causes the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through high affinity interactions with pro-apoptotic BH3 containing proteins, Bak and Bax. Thus targeting Mcl-1 with small molecule inhibitors is a promising strategy but a very challenging task. Using fragment-based methods and structure-based design, we discovered a novel class of potent Mcl-1 inhibitors that exhibit selective anti-proliferative activity. New leads containing a tricyclic indole lactam scaffold exhibited dissociation constants of 1000-fold selectivity for Mcl-1 over Bcl-xLand Bcl-2. They also promoted apoptosis only in Mcl-1 sensitive cancer cell lines by activating caspases in a dose-dependent manner. These results provide a strong proof of concept for a selective inhibition of Mcl-1 function as an effective anti-cancer therapy. Finally, our leads also possess desirable pharmaceutical properties including in vivo oral bioavailability and represent an ideal starting point for developing clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers. Citation Format: Taekyu Lee, Zhiguo Bian, Johannes Belmar, Subrata Shaw, James C. Tarr, Bin Zhao, Nick Pelz, DeMarco Camper, Craig M. Goodwin, Allison L. Arnold, John L. Sensintaffar, Carrie F. Browning, Olivia W. Rossanese, Edward T. Olejniczak, Stephen W. Fesik. Discovery of orally bioavailable novel Mcl-1 inhibitors that exhibit selective anti-proliferative activity in Mcl-1 sensitive cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3551.