8YLB
Cocrystal structures of agonists compound 1 with HsClpP
This is a non-PDB format compatible entry.
Summary for 8YLB
| Entry DOI | 10.2210/pdb8ylb/pdb |
| Descriptor | ATP-dependent Clp protease proteolytic subunit, mitochondrial, 5-[(2-methylphenyl)methyl]-11-(phenylmethyl)-2,5,7,11-tetrazatricyclo[7.4.0.0^{2,6}]trideca-1(9),6-dien-8-one (3 entities in total) |
| Functional Keywords | homo sapiens casein lysing protease p (hsclpp) acute myeloid leukemia (aml) agonists, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 14 |
| Total formula weight | 342710.00 |
| Authors | |
| Primary citation | Xiang, X.,Dai, Z.,Luo, B.,Zhao, N.,Liu, S.,Sui, J.,Huang, J.,Zhou, Y.,Gu, J.,Zhang, J.,Yang, T.,Bao, R.,Luo, Y. Rational Design of a Novel Class of Human ClpP Agonists through a Ring-Opening Strategy with Enhanced Antileukemia Activity. J.Med.Chem., 67:6769-6792, 2024 Cited by PubMed Abstract: The activation of Casein lysing protease P (HsClpP) by a chemical or genetic strategy has been proved to be a new potential therapy in acute myeloid leukemia (AML). However, limited efficacy has been achieved with classic agonist imipridone . Here, a novel class of HsClpP agonists is designed and synthesized using a ring-opening strategy based on the lead compound reported in our previous study. Among these novel scaffold agonists, compound exhibited remarkably enhanced proteolytic activity of HsClpP (EC = 0.79 ± 0.03 μM) and antitumor activity (IC = 0.038 ± 0.003 μM). Moreover, the intraperitoneal administration of compound markedly suppressed tumor growth in Mv4-11 xenograft models, achieving a tumor growth inhibition rate of 88%. Concurrently, displayed advantageous pharmacokinetic properties . This study underscores the promise of compound as a significant HsClpP agonist and an antileukemia drug candidate, warranting further exploration for AML treatment. PubMed: 38620134DOI: 10.1021/acs.jmedchem.4c00338 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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