9CBT

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

Summary for 9CBT

• Entry DOI: 10.2210/pdb9cbt/pdb
• Descriptor: 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)
• Functional Keywords: deacetylase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 65355.80

Authors

Fenwick, M.K.,Young, H.J.,Lin, H. (deposition date: 2024-06-20, release date: 2024-08-07, Last modification date: 2025-02-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.95 Å)