9AQZ

Crystal structure of Bcl-xL in complex with a small molecule inhibitor

これはPDB形式変換不可エントリーです。

9AQZ の概要

• エントリーDOI: 10.2210/pdb9aqz/pdb
• 分子名称: Bcl-2-like protein 1, (3M)-3-(1-{[(1r,3R,5S,7r)-adamantan-1-yl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-{8-[(1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic acid, CADMIUM ION, ... (4 entities in total)
• 機能のキーワード: bcl-xl, apoptosis, inhibitor
• 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: 19573.45

構造登録者

Judge, R.A.,Judd, A.S. (登録日: 2024-02-22, 公開日: 2024-10-16, 最終更新日: 2024-11-20)

主引用文献

Judd, A.S.,Bawa, B.,Buck, W.R.,Tao, Z.F.,Li, Y.,Mitten, M.J.,Bruncko, M.,Catron, N.,Doherty, G.,Durbin, K.R.,Enright, B.,Frey, R.,Haasch, D.,Haman, S.,Haight, A.R.,Henriques, T.A.,Holms, J.,Izeradjene, K.,Judge, R.A.,Jenkins, G.J.,Kunzer, A.,Leverson, J.D.,Martin, R.L.,Mitra, D.,Mittelstadt, S.,Nelson, L.,Nimmer, P.,Palma, J.,Peterson, R.,Phillips, D.C.,Ralston, S.L.,Rosenberg, S.H.,Shen, X.,Song, X.,Vaidya, K.R.,Wang, X.,Wang, J.,Xiao, Y.,Zhang, H.,Zhang, X.,Blomme, E.A.,Boghaert, E.R.,Kalvass, J.C.,Phillips, A.,Souers, A.J.
BCL-X L -targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.
Sci Adv, 10:eado7120-eado7120, 2024

PubMed Abstract: Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-X) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-X inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-X inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-X-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-X-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-X-targeting agent to enter human clinical trials.

PubMed: 39365864
DOI: 10.1126/sciadv.ado7120

実験手法

X-RAY DIFFRACTION (1.961 Å)