Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library ScreenClick to copy article linkArticle link copied!
- Koen F. W. Hekking*Koen F. W. Hekking*Email: [email protected]Symeres, 6546BB Nijmegen, The NetherlandsMore by Koen F. W. Hekking
- Sergio Maroto
- Kees van Kekem
- Frank S. Haasjes
- Jack C. Slootweg
- Patrick G. B. Oude Alink
- Ron Dirks
- Malvika Sardana
- Marjon G. Bolster
- Brian Kuijpers
- Dennis Smith
- Robin Doodeman
- Marcel Scheepstra
- Birgit Zech
- Mark Mulvihill
- Louis M. Renzetti
- Lee Babiss
- Paolo A. CentrellaPaolo A. CentrellaX-Chem, Inc., Waltham, Massachusetts 02453, United StatesMore by Paolo A. Centrella
- Matthew A. Clark
- John W. Cuozzo
- Marie-Aude Guié
- Eric Sigel
- Sevan Habeshian
- Christopher D. HuppChristopher D. HuppX-Chem, Inc., Waltham, Massachusetts 02453, United StatesMore by Christopher D. Hupp
- Julie Liu
- Heather A. ThomsonHeather A. ThomsonX-Chem, Inc., Waltham, Massachusetts 02453, United StatesMore by Heather A. Thomson
- Ying Zhang
- Anthony D. Keefe*Anthony D. Keefe*Email: [email protected]X-Chem, Inc., Waltham, Massachusetts 02453, United StatesMore by Anthony D. Keefe
- Gerhard Müller
- Stijn Gremmen
Abstract
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.
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