Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded
Koen F W Hekking1, Sergio Maroto1, Kees van Kekem1
1Symeres, 6546BB Nijmegen, The Netherlands.
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.
Insights
Researchers developed novel macrocyclic compounds that inhibit myeloid cell leukemia 1 (Mcl-1), a protein linked to cancer growth and drug resistance. This approach offers a promising new avenue for developing targeted cancer therapies.
Area of Science:
- Medicinal Chemistry
- Chemical Biology
- Drug Discovery
Background:
- Evasion of apoptosis is a hallmark of cancer, contributing to tumor development and growth.
- Myeloid cell leukemia 1 (Mcl-1), a pro-survival protein in the Bcl-2 family, is implicated in tumor aggressiveness, poor prognosis, and resistance to therapies.
- Targeting Mcl-1 often involves inhibiting protein-protein interactions, which typically requires complex, large molecules and extensive optimization.
Purpose of the Study:
- To develop novel, potent inhibitors of Mcl-1 using an innovative drug discovery approach.
- To generate conformationally constrained macrocyclic compounds as Mcl-1 inhibitors.
- To identify lead candidates with optimized potency and favorable physicochemical properties for therapeutic development.
Main Methods:
- Utilized DNA-encoded chemical library synthesis and screening to identify initial hit compounds.
- Employed a combination of conformational analysis and structure-based design for optimization.
- Leveraged a robust synthetic platform for rapid analoging and property fine-tuning.
Main Results:
- Successfully generated complex, conformationally privileged macrocyclic Mcl-1 inhibitors.
- Optimized the in vitro potency of a lead series to the low nanomolar range.
- Identified lead candidates (compounds 57/59) with a balanced profile of potency and physicochemical properties.
Conclusions:
- DNA-encoded chemical libraries combined with structure-based design provide an efficient route to complex macrocyclic inhibitors.
- The identified macrocyclic compounds represent promising lead candidates for Mcl-1 targeted cancer therapy.
- These findings pave the way for further preclinical development of novel anti-cancer agents.
