8QSO

Crystal structure of human Mcl-1 in complex with compound 1

Summary for 8QSO

• Entry DOI: 10.2210/pdb8qso/pdb
• Descriptor: Maltose/maltodextrin-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (13S,16R,19S)-16-benzyl-43-ethoxy-N-methyl-7,11,14,17-tetraoxo-13-phenyl-5-oxa-2,8,12,15,18-pentaaza-1(1,4),4(1,2)-dibenzena-9(1,4)-cyclohexanacycloicosaphane-19-carboxamide, ... (4 entities in total)
• Functional Keywords: mcl-1, inhibitor, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 58456.14

Authors

Hekking, K.F.W.,Gremmen, S.,Maroto, S.,Keefe, A.D.,Zhang, Y. (deposition date: 2023-10-10, release date: 2024-02-14, Last modification date: 2024-03-06)

Primary citation

Hekking, K.F.W.,Maroto, S.,van Kekem, K.,Haasjes, F.S.,Slootweg, J.C.,Oude Alink, P.G.B.,Dirks, R.,Sardana, M.,Bolster, M.G.,Kuijpers, B.,Smith, D.,Doodeman, R.,Scheepstra, M.,Zech, B.,Mulvihill, M.,Renzetti, L.M.,Babiss, L.,Centrella, P.A.,Clark, M.A.,Cuozzo, J.W.,Guie, M.A.,Sigel, E.,Habeshian, S.,Hupp, C.D.,Liu, J.,Thomson, H.A.,Zhang, Y.,Keefe, A.D.,Muller, G.,Gremmen, S.
Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.
J.Med.Chem., 67:3039-3065, 2024

PubMed 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 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 / with a balanced profile, which are suitable for future development toward therapeutic use.

PubMed: 38306405
DOI: 10.1021/acs.jmedchem.3c02206

Experimental method

X-RAY DIFFRACTION (2.106 Å)