1区 · 医学
Article
作者: Liu, Julie ; Keefe, Anthony D ; Haasjes, Frank S ; Maroto, Sergio ; Hekking, Koen F W ; Zech, Birgit ; Clark, Matthew A ; Renzetti, Louis M ; Babiss, Lee ; Mulvihill, Mark ; Cuozzo, John W ; Kuijpers, Brian ; Centrella, Paolo A ; Sardana, Malvika ; Dirks, Ron ; Bolster, Marjon G ; Guié, Marie-Aude ; Sigel, Eric ; Hupp, Christopher D ; Smith, Dennis ; Gremmen, Stijn ; Oude Alink, Patrick G B ; Slootweg, Jack C ; Doodeman, Robin ; Scheepstra, Marcel ; Zhang, Ying ; van Kekem, Kees ; Thomson, Heather A ; Müller, Gerhard ; Habeshian, Sevan
Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.