7NB4

Structure of Mcl-1 complex with compound 1

7NB4 の概要

• エントリーDOI: 10.2210/pdb7nb4/pdb
• 関連するPDBエントリー: 6ybl
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, (2~{R})-2-[[5-(3-chloranyl-2-methyl-phenyl)-6-ethyl-thieno[2,3-d]pyrimidin-4-yl]amino]-3-phenyl-propanoic acid, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: apoptosis, apoptosis-inhibitor complex, mcl-1, s64315, small molecule inhibitor, sbdd
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20235.76

構造登録者

Dokurno, P.,Surgenor, A.E.,Kotschy, A. (登録日: 2021-01-25, 公開日: 2021-10-13, 最終更新日: 2024-01-31)

主引用文献

Sipos, S.,Balint, B.,Szabo, Z.B.,Ondi, L.,Csekei, M.,Szlavik, Z.,Proszenyak, A.,Murray, J.B.,Davidson, J.,Chen, I.,Dokurno, P.,Surgenor, A.E.,Pedder, C.,Hubbard, R.E.,Maragno, A.L.,Chanrion, M.,Colland, F.,Geneste, O.,Kotschy, A.
The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.
Acs Omega, 6:22073-22102, 2021

PubMed Abstract: Following the identification of thieno[2,3-]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. As the project approached selection of a clinical candidate, a series of core swap analogues were also prepared. The affinity and cellular activity of these compounds showed a significant dependence on the core structure. In certain cases, we also observed an increased and accelerated epimerization of the atropoisomers. The most potent core replacement analogues showed considerable PD response. One compound was progressed into efficacy studies and inhibited tumor growth.

PubMed: 34497901
DOI: 10.1021/acsomega.1c02595

実験手法

X-RAY DIFFRACTION (1.9 Å)