6D9X

Discovery of Potent 2-Aryl-6,7-Dihydro-5HPyrrolo[ 1,2-a]imidazoles as WDR5 WIN-site Inhibitors Using Fragment-Based Methods and Structure-Based Design

Summary for 6D9X

• Entry DOI: 10.2210/pdb6d9x/pdb
• Descriptor: WD repeat-containing protein 5, SODIUM ION, 2-phenyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, ... (4 entities in total)
• Functional Keywords: wdr5, win-site, fragment screening, structure-based design, mixed-lineage leukemia, dna binding protein, dna binding protein-inhibitor complex, dna binding protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34598.22

Authors

Phan, J.,Fesik, S.W. (deposition date: 2018-04-30, release date: 2018-09-05, Last modification date: 2023-10-04)

Primary citation

Wang, F.,Jeon, K.O.,Salovich, J.M.,Macdonald, J.D.,Alvarado, J.,Gogliotti, R.D.,Phan, J.,Olejniczak, E.T.,Sun, Q.,Wang, S.,Camper, D.,Yuh, J.P.,Shaw, J.G.,Sai, J.,Rossanese, O.W.,Tansey, W.P.,Stauffer, S.R.,Fesik, S.W.
Discovery of Potent 2-Aryl-6,7-dihydro-5 H-pyrrolo[1,2- a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design.
J. Med. Chem., 61:5623-5642, 2018

PubMed Abstract: WDR5 is a chromatin-regulatory scaffold protein overexpressed in various cancers and a potential epigenetic drug target for the treatment of mixed-lineage leukemia. Here, we describe the discovery of potent and selective WDR5-WIN-site inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified several chemically distinct hit series that bind to the WIN site within WDR5. Members of a 6,7-dihydro-5 H-pyrrolo[1,2- a]imidazole fragment class were expanded using a structure-based design approach to arrive at lead compounds with dissociation constants <10 nM and micromolar cellular activity against an AML-leukemia cell line. These compounds represent starting points for the discovery of clinically useful WDR5 inhibitors for the treatment of cancer.

PubMed: 29889518
DOI: 10.1021/acs.jmedchem.8b00375

Experimental method

X-RAY DIFFRACTION (1.83 Å)