8WUZ

Development of 2-imino-2,3,5,6,7,8-hexahydropyrido[4,3-d]pyrimidin-4(1H)-one derivatives as human caseinolytic peptidase P (hClpP) activators

Summary for 8WUZ

• Entry DOI: 10.2210/pdb8wuz/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, mitochondrial, 5-[(3-fluorophenyl)methyl]-9-[[4-(trifluoromethyl)phenyl]methyl]-1,5,9,11-tetrazatricyclo[8.4.0.0^{2,7}]tetradeca-2(7),10-dien-8-one, BROMIDE ION (3 entities in total)
• Functional Keywords: mitochondria, caseinolytic protease p, activator, antitumor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 7
• Total formula weight: 173205.70

Authors

Jiang, J.-X.,Ding, H.,Chen, M.-R.,Lu, M.-L.,Sun, H.-Y.,Xiao, Y.-B. (deposition date: 2023-10-22, release date: 2024-10-23, Last modification date: 2025-04-09)

Primary citation

Zhang, Y.,Jiang, J.,Ding, H.,Li, Q.,Xiao, Y.,Sun, H.
Development of novel imipridone derivatives with potent anti-cancer activities as human caseinolytic peptidase P (hClpP) activators.
Bioorg.Chem., 153:107765-107765, 2024

PubMed Abstract: Based on a clinically staged small molecular hClpP activator ONC201, a class of imipridone derivatives was designed and synthesized. These compounds were evaluated in a protease hydrolytic assay, as well as cell growth inhibition assays in three cancer cell lines, MIA PACA-2, HCT116, and MV4-11. A number of compounds that can more potently activate hClpP and more effectively inhibit cell growth in the three cancer cell lines than ONC201 were identified. The most potent compound, ZYZ-17, activated hClpP with an EC value of 0.24 µM and inhibited the growth of the three cancer cell lines with IC values of less than 10 nM. Mechanism studies for ZYZ-17 revealed that it potently activates cellular hClpP, efficiently induces the degradation of hClpP substrates, and robustly induces apoptosis in the three cancer cell lines. Furthermore, ZYZ-17 demonstrated a promising pharmacokinetic (PK) profile and exhibited highly potent in vivo antitumor activity in a pancreatic cancer MIA PACA-2 xenograft model in BALB/c nude mice.

PubMed: 39243740
DOI: 10.1016/j.bioorg.2024.107765

Experimental method

X-RAY DIFFRACTION (2.9 Å)