7AXR
Crystal structure of BRD4(1) bound to the dual BET-HDAC inhibitor LSH24
Summary for 7AXR
| Entry DOI | 10.2210/pdb7axr/pdb |
| Descriptor | Bromodomain-containing protein 4, 4-acetyl-3-ethyl-N-(3-(3-(hydroxyamino)-3-oxopropyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (3 entities in total) |
| Functional Keywords | brd4(1), brd4, bd1, first bromodomain, bromodomain, bet, hdac, beti, hdaci, dual inhibitor, lsh24, protein binding |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 15814.19 |
| Authors | Huegle, M. (deposition date: 2020-11-10, release date: 2021-10-06, Last modification date: 2024-01-31) |
| Primary citation | Schaker-Hubner, L.,Warstat, R.,Ahlert, H.,Mishra, P.,Kraft, F.B.,Schliehe-Diecks, J.,Scholer, A.,Borkhardt, A.,Breit, B.,Bhatia, S.,Hugle, M.,Gunther, S.,Hansen, F.K. 4-Acyl Pyrrole Capped HDAC Inhibitors: A New Scaffold for Hybrid Inhibitors of BET Proteins and Histone Deacetylases as Antileukemia Drug Leads. J.Med.Chem., 64:14620-14646, 2021 Cited by PubMed Abstract: Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor and well-established HDAC inhibitors. The most promising new hybrids, and , displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, , induced significantly more apoptosis than the related control compounds (no BRD4(1) affinity) and (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, was well tolerated in an zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds. PubMed: 34582215DOI: 10.1021/acs.jmedchem.1c01119 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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