2. Academic Validation
  3. Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

  • J Med Chem. 2024 Feb 22;67(4):3039-3065. doi: 10.1021/acs.jmedchem.3c02206.
Koen F W Hekking 1,  Sergio Maroto 1,  Kees van Kekem 1,  Frank S Haasjes 1,  Jack C Slootweg 1,  Patrick G B Oude Alink 1,  Ron Dirks 1,  Malvika Sardana 1,  Marjon G Bolster 1,  Brian Kuijpers 1,  Dennis Smith 1,  Robin Doodeman 1,  Marcel Scheepstra 1,  Birgit Zech 2,  Mark Mulvihill 2,  Louis M Renzetti 2,  Lee Babiss 2,  Paolo A Centrella 3,  Matthew A Clark 3,  John W Cuozzo 3,  Marie-Aude Guié 3,  Eric Sigel 3,  Sevan Habeshian 3,  Christopher D Hupp 3,  Julie Liu 3,  Heather A Thomson 3,  Ying Zhang 3,  Anthony D Keefe 3,  Gerhard Müller 1,  Stijn Gremmen 1
Affiliations

Affiliations

  • 1 Symeres, 6546BB Nijmegen, The Netherlands.
  • 2 X-Rx, Inc., New York, New York 10016, United States.
  • 3 X-Chem, Inc., Waltham, Massachusetts 02453, United States.
PMID: 38306405 DOI: 10.1021/acs.jmedchem.3c02206
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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