Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein–Protein Interaction Modulator with the Potential of Treating Hematological Malignancies
Fedor Romanov‐Michailidis, Chien‐Chi Hsiao, Lorenz M. Urner, Soufyan Jerhaoui, Michel Surkyn, Bradley S. Miller, Ann Vos, Maria Dominguez Blanco, Ruud Bueters, Petra Vinken, Mariette Bekkers, David Walker, Beth Pietrak, Werner Eyckmans, José Luís Dores‐Sousa, Seong Joo Koo, William Lento, Marcus Bauser, Ulrike Philippar, Frederik Rombouts
Abstract
Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the “non-Lipinski” beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.