5VFC

WDR5 bound to inhibitor MM-589

Summary for 5VFC

• Entry DOI: 10.2210/pdb5vfc/pdb
• Related PRD ID: PRD_002270
• Descriptor: WD repeat-containing protein 5, N-{(3R,6S,9S,12R)-6-ethyl-12-methyl-9-[3-(N'-methylcarbamimidamido)propyl]-2,5,8,11-tetraoxo-3-phenyl-1,4,7,10-tetraazacyclotetradecan-12-yl}-2-methylpropanamide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, wd repeat, transcription, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 35336.08

Authors

Stuckey, J.A. (deposition date: 2017-04-07, release date: 2017-06-28, Last modification date: 2024-03-13)

Primary citation

Karatas, H.,Li, Y.,Liu, L.,Ji, J.,Lee, S.,Chen, Y.,Yang, J.,Huang, L.,Bernard, D.,Xu, J.,Townsend, E.C.,Cao, F.,Ran, X.,Li, X.,Wen, B.,Sun, D.,Stuckey, J.A.,Lei, M.,Dou, Y.,Wang, S.
Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction.
J. Med. Chem., 60:4818-4839, 2017

PubMed Abstract: We report herein the design, synthesis, and evaluation of macrocyclic peptidomimetics that bind to WD repeat domain 5 (WDR5) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction. Compound 18 (MM-589) binds to WDR5 with an IC value of 0.90 nM (K value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC value of 12.7 nM. Compound 18 potently and selectively inhibits cell growth in human leukemia cell lines harboring MLL translocations and is >40 times better than the previously reported compound MM-401. Cocrystal structures of 16 and 18 complexed with WDR5 provide structural basis for their high affinity binding to WDR5. Additionally, we have developed and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional evaluation of these designed compounds. Compound 18 represents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimization of 18 may yield a new therapy for acute leukemia.

PubMed: 28603984
DOI: 10.1021/acs.jmedchem.6b01796

Experimental method

X-RAY DIFFRACTION (1.64 Å)