7UAS

Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization

Summary for 7UAS

• Entry DOI: 10.2210/pdb7uas/pdb
• Descriptor: WD repeat-containing protein 5, (5P)-2-[(S)-cyclopropyl(4-methylpyridin-2-yl)methyl]-5-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-7-[(2-methyl-1H-imidazol-1-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one (3 entities in total)
• Functional Keywords: wdr5, structure-based design, transcription-transcription inhibitor complex, transcription/transcription inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69879.19

Authors

Zhao, B. (deposition date: 2022-03-14, release date: 2022-05-04, Last modification date: 2023-10-18)

Primary citation

Teuscher, K.B.,Meyers, K.M.,Wei, Q.,Mills, J.J.,Tian, J.,Alvarado, J.,Sai, J.,Van Meveren, M.,South, T.M.,Rietz, T.A.,Zhao, B.,Moore, W.J.,Stott, G.M.,Tansey, W.P.,Lee, T.,Fesik, S.W.
Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.
J.Med.Chem., 65:6287-6312, 2022

PubMed Abstract: WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new lead series. Importantly, this new series of compounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueous solubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition.

PubMed: 35436124
DOI: 10.1021/acs.jmedchem.2c00195

Experimental method

X-RAY DIFFRACTION (1.808 Å)