8QSO

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

8QSO の概要

• エントリーDOI: 10.2210/pdb8qso/pdb
• 分子名称: 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)
• 機能のキーワード: mcl-1, inhibitor, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58456.14

構造登録者

Hekking, K.F.W.,Gremmen, S.,Maroto, S.,Keefe, A.D.,Zhang, Y. (登録日: 2023-10-10, 公開日: 2024-02-14, 最終更新日: 2024-03-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.106 Å)