Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core

Abstract

Author Contributions JT, KBT, JRA, JJM, KMM, RDG, CH, and JDM designed and synthesized compounds. ERA and LRT conducted mechanism of action studies featured in Figure 4,5 and 7. JS and JGS obtained the biochemical and cell-based data in Table 1-3. JLS conducted western blot and caspase assay in Figure 6. BZ, TAR, and WGP performed X-ray crystallography studies of complexes. JK, MI, andRJC conducted CTOSs assay in Figure 8. WJM GMS helped design experiments. WPT, SRS, TL, and SWF design and directed experiments and helped write the paper. All authors have given approval to the final version of the manuscript. Supporting Information. X-ray refinement statistics, MLL1 HMT assay details and titration curves of compound 16. This material is available free of charge via the internet at http://pubs.acs.org. Accession Codes. Atom coordinates and structure factors for WDR5-ligand complexes can be accessed in the PDB via the following accession codes: Compound 13/WDR5 complex (6UFX), Compound 16/WDR5 complex (6UCS). Authors will release the atomic coordinates upon article publication.

Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

“…40 , 41 Other analogues were found to inhibit WDR5 protein–protein interactions, leading to inhibition of cancer cell proliferation. 42 − 44 …”

Structural requirements for dihydrobenzoxazepinone anthelmintics: actions against medically important and model parasites -Trichuris muris,Brugia malayi,Heligmosomoides polygyrusandSchistosoma mansoni

“…DBQs have been investigated quite extensively in medicinal chemistry; examples have been reported as antiviral agents through inhibition of HIV replication [31,32]. Other analogues were found to inhibit WDR5 protein-protein interactions, leading to inhibition of cancer cell proliferation [33–35]. 3-5…”

“…DBQs have been investigated quite extensively in medicinal chemistry; examples have been reported as antiviral agents through inhibition of HIV replication [39,40]. Other analogues were found to inhibit WDR5 protein-protein interactions, leading to inhibition of cancer cell proliferation [41][42][43]. [3][4][5] It was decided to prepare a small number of compounds only using those substituents and comparable regiochemistry that gave the most potent analogues so far.…”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…WDR5 has, thus, emerged as an attractive target for cancer therapeutics. Tian et al synthesized new compounds based on dihydroimidazole imine 148 in which the structure-guided optimization of this compound led to improved WDR5 inhibitory activity, as well as anticancer activity [144]. Replacement of the 4-fluoro-2-methylpyridin-3-yl and 3,4-dichlorobenzyl moieties present in compound 148 with 4-fluoro-2-methylphenyl and 3,5-dimethoxy benzyl groups, respectively, resulted in compound 149.…”