7JMT

Crystal structure of schistosome BCL-2 bound to ABT-737

7JMT の概要

• エントリーDOI: 10.2210/pdb7jmt/pdb
• 分子名称: BCL-2 protein, 4-{4-[(4'-CHLOROBIPHENYL-2-YL)METHYL]PIPERAZIN-1-YL}-N-{[4-({(1R)-3-(DIMETHYLAMINO)-1-[(PHENYLTHIO)METHYL]PROPYL}AMINO)-3-NITROPHENYL]SULFONYL}BENZAMIDE (3 entities in total)
• 機能のキーワード: apoptosis
• 由来する生物種: Schistosoma japonicum (Blood fluke)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 145380.47

構造登録者

Smith, N.A.,Smith, B.J.,Lee, E.F.,Colman, P.M.,Fairlie, W.D. (登録日: 2020-08-02, 公開日: 2021-02-17, 最終更新日: 2023-10-18)

主引用文献

Nguyen, W.,Lee, E.F.,Evangelista, M.,Lee, M.,Harris, T.J.,Colman, P.M.,Smith, N.A.,Williams, L.B.,Jarman, K.E.,Lowes, K.N.,Haeberli, C.,Keiser, J.,Smith, B.J.,Fairlie, W.D.,Sleebs, B.E.
Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.
Acs Infect Dis., 7:1143-1163, 2021

PubMed Abstract: Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold () with potent sBCL-2 activity (IC 30 nM). Human BCL-XL potency (IC 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.

PubMed: 33523649
DOI: 10.1021/acsinfecdis.0c00700

実験手法

X-RAY DIFFRACTION (2.75 Å)