9J6O

Crystal Structure of bromodomain of human CBP in complex with the inhibitor CZL-046

This is a non-PDB format compatible entry.

Summary for 9J6O

• Entry DOI: 10.2210/pdb9j6o/pdb
• Descriptor: CREB-binding protein, (3~{S},5~{S})-1-[3,4-bis(fluoranyl)phenyl]-5-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1-(4-methoxycyclohexyl)benzimidazol-2-yl]-3-fluoranyl-pyrrolidin-2-one, CHLORIDE ION (3 entities in total)
• Functional Keywords: bromodomain, cbp, inhibitor, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 16465.31

Authors

Zhang, Y.,Zhang, C.,Chen, Z.,Yang, H.,Huang, X.,Li, Y.,Xu, Y. (deposition date: 2024-08-16, release date: 2024-10-16, Last modification date: 2024-11-06)

Primary citation

Chen, Z.,Yang, H.,Zhang, Y.,Lyu, X.,Shi, Q.,Zhang, C.,Wang, X.,Wang, Z.,Zhang, Y.,Deng, Y.,Wang, Y.,Huang, Y.,Xu, Y.,Huang, X.,Li, Y.
Discovery of CZL-046 with an ( S )-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.
J.Med.Chem., 67:18606-18628, 2024

PubMed Abstract: E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an ()-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC = 51.5 nM). suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound , exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with provides an insight into the precise binding mode. The results demonstrate that is a promising p300 bromodomain inhibitor for the treatment of MM.

PubMed: 39356741
DOI: 10.1021/acs.jmedchem.4c01984

Experimental method

X-RAY DIFFRACTION (2.67 Å)