5KU9

Crystal structure of MCL1 with compound 1

5KU9 の概要

• エントリーDOI: 10.2210/pdb5ku9/pdb
• 分子名称: Induced myeloid leukemia cell differentiation protein Mcl-1, SODIUM ION, (3~{S})-3-azanyl-4-(4-bromophenyl)-~{N}-[(3~{S})-1-[2-[[(2~{R})-1-(3,4-dichlorophenyl)-4-(methylamino)-4-oxidanylidene-butan-2-yl]amino]-2-oxidanylidene-ethyl]-2-oxidanylidene-4,5-dihydro-3~{H}-1-benzazepin-3-yl]butanamide, ... (4 entities in total)
• 機能のキーワード: inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: MUS MUSCULUS, HOMO SAPIENS (mouse, human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 37913.13

構造登録者

Ferguson, A.D. (登録日: 2016-07-13, 公開日: 2017-01-11, 最終更新日: 2023-10-04)

主引用文献

Johannes, J.W.,Bates, S.,Beigie, C.,Belmonte, M.A.,Breen, J.,Cao, S.,Centrella, P.A.,Clark, M.A.,Cuozzo, J.W.,Dumelin, C.E.,Ferguson, A.D.,Habeshian, S.,Hargreaves, D.,Joubran, C.,Kazmirski, S.,Keefe, A.D.,Lamb, M.L.,Lan, H.,Li, Y.,Ma, H.,Mlynarski, S.,Packer, M.J.,Rawlins, P.B.,Robbins, D.W.,Shen, H.,Sigel, E.A.,Soutter, H.H.,Su, N.,Troast, D.M.,Wang, H.,Wickson, K.F.,Wu, C.,Zhang, Y.,Zhao, Q.,Zheng, X.,Hird, A.W.
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors.
ACS Med Chem Lett, 8:239-244, 2017

PubMed Abstract: Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC of 3 μM after 6 h.

PubMed: 28197319
DOI: 10.1021/acsmedchemlett.6b00464

実験手法

X-RAY DIFFRACTION (2.2 Å)