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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.

Wang, Feng and Jeon, Kyu Ok and Salovich, James M and Macdonald, Jonathan D and Alvarado, Joseph and Gogliotti, Rocco D and Phan, Jason and Olejniczak, Edward T and Sun, Qi and Wang, Shidong and Camper, DeMarco and Yuh, Joannes P and Shaw, J Grace and Sai, Jiqing and Rossanese, Olivia W and Tansey, William P and Stauffer, Shaun R and Fesik, Stephen W (2018) 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. Journal of medicinal chemistry, 61 (13). pp. 5623-5642. ISSN 1520-4804

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.

Item Type: Article
Date Deposited: 28 Mar 2019 00:45
Last Modified: 28 Mar 2019 00:45
URI: https://oak.novartis.com/id/eprint/39349

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