4HW4

Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design

4HW4 の概要

• エントリーDOI: 10.2210/pdb4hw4/pdb
• 関連するPDBエントリー: 4HW2 4HW3 4HW4
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Mcl-1 BH3 peptide (3 entities in total)
• 機能のキーワード: anti-apoptotic protein, bh3 peptides, apoptosis
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass membrane protein (Potential): Q07820
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 39398.73

構造登録者

Friberg, A.,Zhao, B. (登録日: 2012-11-07, 公開日: 2013-01-09, 最終更新日: 2024-10-30)

主引用文献

Friberg, A.,Vigil, D.,Zhao, B.,Daniels, R.N.,Burke, J.P.,Garcia-Barrantes, P.M.,Camper, D.,Chauder, B.A.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.
J.Med.Chem., 56:15-30, 2013

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.

PubMed: 23244564
DOI: 10.1021/jm301448p

実験手法

X-RAY DIFFRACTION (1.53 Å)