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
  • 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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