9CBT

Crystal structure of human sirtuin 3 fragment (residues 118-399) bound to intermediates from reaction with NAD and inhibitor NH6-10

9CBT の概要

• エントリーDOI: 10.2210/pdb9cbt/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, ZINC ION, 2-{[(2S)-6-[(Z)-(1-{[(2R,3R,4R,5R)-5-({[(R)-{[(R)-{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}methyl)-4-hydroxy-2-sulfanyloxolan-3-yl]oxy}tetradecylidene)amino]-2-{[(benzyloxy)carbonyl]amino}hexanoyl]amino}-N,N,N-triethylethan-1-aminium (non-preferred name), ... (6 entities in total)
• 機能のキーワード: deacetylase, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65355.80

構造登録者

Fenwick, M.K.,Young, H.J.,Lin, H. (登録日: 2024-06-20, 公開日: 2024-08-07, 最終更新日: 2025-02-19)

主引用文献

Jana, S.,Shang, J.,Hong, J.Y.,Fenwick, M.K.,Puri, R.,Lu, X.,Melnick, A.M.,Li, M.,Lin, H.
A Mitochondria-Targeting SIRT3 Inhibitor with Activity against Diffuse Large B Cell Lymphoma.
J.Med.Chem., 67:15428-15437, 2024

PubMed Abstract: Diffuse large B-cell lymphomas (DLBCLs) are heterogeneous cancers that still require better and less toxic treatments. SIRT3, a member of the sirtuin family of NAD-dependent protein deacylase, is critical for DLBCL growth and survival. A mitochondria-targeted SIRT3 small-molecule inhibitor, YC8-02, exhibits promising activity against DLBCL. However, YC8-02 has several limitations including poor solubility. Here, we report our medicinal chemistry efforts that led to an improved mitochondria-targeted SIRT3 inhibitor, SJ-106C, achieved by using a triethylammonium group, which helps to increase both solubility and SIRT3 inhibition potency. SJ-106C, while still inhibiting SIRT1 and SIRT2, is enriched in the mitochondria to help with SIRT3 inhibition. It is more active against DLBCL than other solid tumor cells and effectively inhibits DLBCL xenograft tumor growth. The findings provide useful insights for the development of SIRT3 inhibitors and mitochondrial targeting agents and further support the notion that SIRT3 is a promising druggable target for DLBCL.

PubMed: 39191393
DOI: 10.1021/acs.jmedchem.4c01053

実験手法

X-RAY DIFFRACTION (1.95 Å)