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

Autor: Hekking KFW; Symeres, 6546BB Nijmegen, The Netherlands., Maroto S; Symeres, 6546BB Nijmegen, The Netherlands., van Kekem K; Symeres, 6546BB Nijmegen, The Netherlands., Haasjes FS; Symeres, 6546BB Nijmegen, The Netherlands., Slootweg JC; Symeres, 6546BB Nijmegen, The Netherlands., Oude Alink PGB; Symeres, 6546BB Nijmegen, The Netherlands., Dirks R; Symeres, 6546BB Nijmegen, The Netherlands., Sardana M; Symeres, 6546BB Nijmegen, The Netherlands., Bolster MG; Symeres, 6546BB Nijmegen, The Netherlands., Kuijpers B; Symeres, 6546BB Nijmegen, The Netherlands., Smith D; Symeres, 6546BB Nijmegen, The Netherlands., Doodeman R; Symeres, 6546BB Nijmegen, The Netherlands., Scheepstra M; Symeres, 6546BB Nijmegen, The Netherlands., Zech B; X-Rx, Inc., New York, New York 10016, United States., Mulvihill M; X-Rx, Inc., New York, New York 10016, United States., Renzetti LM; X-Rx, Inc., New York, New York 10016, United States., Babiss L; X-Rx, Inc., New York, New York 10016, United States., Centrella PA; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Clark MA; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Cuozzo JW; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Guié MA; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Sigel E; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Habeshian S; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Hupp CD; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Liu J; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Thomson HA; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Zhang Y; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Keefe AD; X-Chem, Inc., Waltham, Massachusetts 02453, United States., Müller G; Symeres, 6546BB Nijmegen, The Netherlands., Gremmen S; Symeres, 6546BB Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Feb 22; Vol. 67 (4), pp. 3039-3065. Date of Electronic Publication: 2024 Feb 02.
DOI: 10.1021/acs.jmedchem.3c02206
Abstrakt: 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.
Databáze: MEDLINE
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