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

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 in vivo 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.

Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models

“…We recently reported a class of WDR5 WIN-site inhibitors that exhibited high on-target potency, improved physicochemical properties, and good oral PK profiles ( 45 ). The structure of representative compound 1 ( Fig.…”

“…The anchored core provides the appropriate exit vectors for the P 2 , P 4 , and P 7 pharmacophore units to extend to the S 2 , S 4 , and S 7 binding subsites, respectively ( Fig. 2 C ) ( 41 , 45 ). Both N -linked imidazole and 2-methyl imidazole are P 2 pharmacophore units that form the critical sandwiched π – π stacking interactions with WDR5 residues F133 and F263 in the S 2 subsite ( Fig.…”

“…Furthermore, they exhibited mild antiproliferative activities in WDR5-sensitive cancer cells ( 35 , 36 , 42 ). We have also reported the discovery of highly potent WDR5 WIN-site inhibitors that were obtained using fragment-based methods and structure-based design ( 41 , 43 – 45 ). Our early small-molecule probes C6 ( 44 ) and C16 ( 41 ) are highly potent WDR5 inhibitors that display robust antiproliferative activity against the MV4:11 cell line and have been utilized to investigate the cellular effect of WIN-site inhibition.…”

“…However, there have been no reported WDR5 inhibitors or PROTACs that achieve significant in vivo efficacy at a pharmacologically relevant dose by oral administration in preclinical cancer models. Recently, we discovered a series of highly potent and orally bioavailable WDR5 WIN-site inhibitors using a pharmacophore-based optimization method ( 45 ). Here, we report our continued efforts to further optimize the potency, druglike properties, and PK profiles of WDR5 WIN-site inhibitors.…”

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

“…7B ). Recently published work using C16-related WDR5 small molecule inhibitors also found no systemic toxicity and did not note any neurologic defects, noting a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability (Teuscher et al, 2022). Mouse and human WDR5 are identical (Guarnaccia and Tansey, 2018), therefore C16 is predicted to bind mouse WDR5 and in this sense, toxicity studies with WDR5 inhibitors in mice are translatable to humans.…”