6QFM

Structure of human Mcl-1 in complex with PUMA BH3 peptide

6QFM の概要

• エントリーDOI: 10.2210/pdb6qfm/pdb
• 関連するPDBエントリー: 6qfi
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, Bcl-2-binding component 3, ZINC ION, ... (5 entities in total)
• 機能のキーワード: apoptosis, mcl1, bcl2, puma
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 21403.44

構造登録者

Dokurno, P.,Murray, J.,Davidson, J.,Chen, I.,Davis, B.,Graham, C.J.,Harris, R.,Jordan, A.M.,Matassova, N.,Pedder, C.,Ray, S.,Roughley, S.,Smith, J.,Walmsley, C.,Wang, Y.,Whitehead, N.,Williamson, D.S.,Casara, P.,Le Diguarher, T.,Hickman, J.,Stark, J.,Kotschy, A.,Geneste, O.,Hubbard, R.E. (登録日: 2019-01-10, 公開日: 2019-06-12, 最終更新日: 2024-01-24)

主引用文献

Murray, J.B.,Davidson, J.,Chen, I.,Davis, B.,Dokurno, P.,Graham, C.J.,Harris, R.,Jordan, A.,Matassova, N.,Pedder, C.,Ray, S.,Roughley, S.D.,Smith, J.,Walmsley, C.,Wang, Y.,Whitehead, N.,Williamson, D.S.,Casara, P.,Le Diguarher, T.,Hickman, J.,Stark, J.,Kotschy, A.,Geneste, O.,Hubbard, R.E.
Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.
Acs Omega, 4:8892-8906, 2019

PubMed Abstract: We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using H and N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

PubMed: 31459977
DOI: 10.1021/acsomega.9b00611

実験手法

X-RAY DIFFRACTION (2 Å)