4YAB

Crystal structure of TRIM24 PHD-bromodomain complexed with 1-methyl-5-(2-methyl-1 3-thiazol-4-yl)-2 3-dihydro-1H-indol-2-one (1)

Summary for 4YAB

• Entry DOI: 10.2210/pdb4yab/pdb
• Related: 4YAD 4YAT 4YAX 4YBM 4YBS 4YBT 4YC9
• Descriptor: Transcription intermediary factor 1-alpha, ZINC ION, 1-methyl-5-(2-methyl-1,3-thiazol-4-yl)-1,3-dihydro-2H-indol-2-one, ... (5 entities in total)
• Functional Keywords: center for biomolecular structure and function, bromodomain, trim24, inhibitor, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O15164
• Total number of polymer chains: 2
• Total formula weight: 43579.18

Authors

Poncet-Montange, G.,Palmer, W.,Jones, P. (deposition date: 2015-02-17, release date: 2015-06-24, Last modification date: 2023-09-27)

Primary citation

Palmer, W.S.,Poncet-Montange, G.,Liu, G.,Petrocchi, A.,Reyna, N.,Subramanian, G.,Theroff, J.,Yau, A.,Kost-Alimova, M.,Bardenhagen, J.P.,Leo, E.,Shepard, H.E.,Tieu, T.N.,Shi, X.,Zhan, Y.,Zhao, S.,Barton, M.C.,Draetta, G.,Toniatti, C.,Jones, P.,Geck Do, M.,Andersen, J.N.
Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor.
J.Med.Chem., 59:1440-1454, 2016

PubMed Abstract: The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.

PubMed: 26061247
DOI: 10.1021/acs.jmedchem.5b00405

Experimental method

X-RAY DIFFRACTION (1.9 Å)