Wang, Feng, Jeon, Kyu Ok, Salovich, James M, Macdonald, Jonathan D, Alvarado, Joseph, Gogliotti, Rocco D, Phan, Jason, Olejniczak, Edward T, Sun, Qi, Wang, Shidong, Camper, DeMarco, Yuh, Joannes P, Shaw, J Grace, Sai, Jiqing, Rossanese, Olivia W, Tansey, William P, 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