Discovery of Potent 2-Aryl-6,7-dihydro-5<i>H</i>-pyrrolo[1,2-<i>a</i>]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

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 V.; Yuh, Joannes P.; Shaw, J. Grace; Sai, Jiqing; Rossanese, Olivia W.; Tansey, William P.; Stauffer, Shaun R.; Fesik, Stephen W.

doi:10.1021/acs.jmedchem.8b00375

Cited by 57 publications

(64 citation statements)

References 37 publications

(83 reference statements)

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“…While the zero atom linker showed little binding ( 13 , K D = 5.2 mM), a linker length of one, two, or three methylene units was tolerated ( 14 , K D = 530 μ M, 15 , K D = 300 μ M, and 16 , K D = 140 μ M, respectively). Interestingly, the weakly binding fragment 13 is similar to the imidazole fragment hit reported by Wang et al 28 The subtle difference in orientation between the two series' imidazole rings appears key to avoid clashes with nearby residues S49 and I305. A cocrystal structure bound with 16 was solved, showing the introduced phenyl ring projecting into subpocket S4, toward residues A47, S49, A65, and L321 [Fig.…”

Section: Resultssupporting

confidence: 59%

“…This compound inhibits the histone methyltransferase (HMT) activity of MLL1 in vitro and reduces the viability of primary human AML cells bearing C/EBPα mutations 24 and inhibits “gain-of-function” p53 cell growth 26 . Recently, an NMR-based fragment screen identified several high-affinity WIN-site binders 28,29 . These compounds show cellular activity through displacement of WDR5 from chromatin, an effect that gives WDR5 inhibitors therapeutic relevance beyond MLL-r cancers 29 .…”

Section: Introductionmentioning

confidence: 99%

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Fragment screening for a protein-protein interaction inhibitor to WDR5

Dennis

Morrow

Dolezal

et al. 2019

Structural Dynamics

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The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the “WIN” site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign—guided by a suite of high-resolution cocrystal structures with WDR5—progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 Å) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (kd = ∼0.06 s−1) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.

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Section: Resultssupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Fragment screening for a protein-protein interaction inhibitor to WDR5

Dennis

Morrow

Dolezal

et al. 2019

Structural Dynamics

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“…To identify small molecules that bind the WIN site, we conducted a fragment-based screen of ~13,800 compounds by acquiring SOFAST 1 H- 15 N heteronuclear multiple quantum coherence (HMQC) spectra of WDR5 ( Wang et al, 2018 ). An initial HMQC spectrum of uniformly 15 N-labeled WDR5 with an unlabeled MLL1 WIN peptide highlighted peak shifts that correspond to amino acids in the vicinity of the WIN site.…”

Section: Resultsmentioning

confidence: 99%

“…One of these fragment hits is compound C1 ( Figure 1A ), which binds WDR5 with a K d of ~66 μM ( Table S1 ). We solved the X-ray crystal structure of C1 when complexed with WDR5 ( Figure 1B ; Table S2 ) and found that the cyclic guanidine of C1 binds deep into the S 2 pocket of WDR5 ( Wang et al, 2018 ), mimicking the arginine of the WIN peptide. To improve the affinity of C1, we used structure-based design to access nearby pockets.…”

Section: Resultsmentioning

confidence: 99%

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

et al. 2019

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SUMMARY The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the “WIN site” of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes. WIN site inhibitors rapidly displace WDR5 from chromatin and decrease the expression of associated genes, causing translational inhibition, nucleolar stress, and p53 induction. Our studies define a mode by which WDR5 engages chromatin and forecast that WIN site blockade could have utility against multiple cancer types.

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“…This result has clinical significance because there are now several small molecule inhibitors of WDR5 used in both in vitro and in vivo studies, including OICR-9429 [25]. There are also more specific emerging inhibitors of WDR5 with a higher IC 50 that have been recently developed [26]. The available targeted drugs for patients with advanced-stage papillary thyroid carcinoma remain limited.…”

Section: Discussionmentioning

confidence: 99%

Expression of WD Repeat Domain 5 (WDR5) is Associated with Progression and Reduced Prognosis in Papillary Thyroid Carcinoma

Wang

et al. 2019

Med Sci Monit

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Background The WD repeat domain 5 (WDR5) is an essential component of methyltransferase complexes. The expression of WDR5 has been reported in several types of malignancy. This study aimed to investigate the expression of the WDR5 gene and protein in a human papillary carcinoma cell line in vitro , including the use WDR5 gene silencing, and the expression of the WDR5 protein in papillary thyroid carcinoma tissue, and clinicopathological characteristics including overall survival (OS). Material/Methods The role of WDR5 in proliferation and migration of the human papillary thyroid carcinoma cell line, KTC-1, was investigated using the cell counting kit-8 (CCK-8) assay and transwell assay after silencing WDR5 expression. Expression levels of WDR5 in 84 patients with papillary thyroid carcinoma were detected using immunohistochemistry. The correlation between WDR5 expression and clinicopathological features was analyzed using the chi-squared test. The prognostic role of WDR5 was evaluated by univariate analysis with the log-rank test, and by multivariate analysis with the Cox regression model. Results WDR5 expression promoted the proliferation and migration of the KTC-1 cells. In tumor tissue from patients with papillary thyroid carcinoma, low expression and high expression levels of WDR5 were found in 72.6% and 27.4%, respectively. Increased expression of WDR5 was significantly associated with lymphatic invasion and reduced survival rates. WDR5 expression was an independent negative prognostic biomarker. Conclusions Expression of WDR5 promoted cell proliferation and migration in vitro and was associated with reduced prognosis in patients with papillary thyroid carcinoma.

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Discovery of Potent 2-Aryl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazoles as WDR5-WIN-Site Inhibitors Using Fragment-Based Methods and Structure-Based Design

Cited by 57 publications

References 37 publications

Fragment screening for a protein-protein interaction inhibitor to WDR5

Fragment screening for a protein-protein interaction inhibitor to WDR5

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity

Expression of WD Repeat Domain 5 (WDR5) is Associated with Progression and Reduced Prognosis in Papillary Thyroid Carcinoma

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