Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4+ T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.
Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein–protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a K d of 3.4 μM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.
The Amaryllidaceae alkaloid trans-dihydrolycoricidine 7 and three analogues 8−10 were produced via asymmetric chemical synthesis. Alkaloid 7 proved superior to acyclovir, the current standard for herpes simplex virus, type 1 (HSV-1) infection. Compound 7 potently inhibited lytic HSV-1 infection, significantly reduced HSV-1 reactivation, and more potently inhibited varicella zoster virus (VZV) lytic infection. A configurationally defined (3R)-secondary alcohol at C3 proved crucial for efficacious inhibition of lytic HSV-1 infection. KEYWORDS: Herpesvirus, HSV-1, varicella zoster, stem cells, Amaryllidaceae, alkaloid H erpes simplex virus, type 1 (HSV-1) is a ubiquitous DNA virus from the Herpesviridae family that causes substantial human morbidity and mortality. 1 With seropositivity rates exceeding 70% in elders, it causes recurrent cold sores, corneal infection, blindness, and, rarely, encephalitis. 1 It establishes latent infection in sensory neurons that is refractory to clearance, producing an intractable lifelong reservoir that cycles with lytic infections. Though acute HSV-1 infection is readily treatable with nontoxic nucleoside analogues such as acyclovir (ACV), no drug successfully eliminates the latent infection. In addition, growing ACV drug resistance has further fueled the search for novel antivirals. 2 Plants of the Amaryllidaceae family produce numerous structurally diverse, biologically active alkaloids. 3,4 In particular, alkaloids of the lycorane subclass including lycorine 1, pseudolycorine 2, pancratistatin 3, its 7-deoxy analogue 4, and the unsaturated derivatives narciclasine 5 and deoxy analogue 6 have demonstrated a variety of antiviral activities (Figure 1). 5−13 The restricted availability of other natural lycorane-type alkaloids and the absence of a rapid synthetic route toward structural analogues has impeded further development of the antiviral pharmacophore.The development of synthetic strategies that allow rapid access to functionally dense, stereochemically defined cores not only enables the asymmetric synthesis of biologically active natural products, but opens synthetic entry to non-natural analogues. These analogues expand the structural diversity are natural products. Compounds 7−10 were accessed via total synthesis. Lycorine 1, pseudolycorine 2, pancratistatin 3, 7-deoxypancratistatin 4, narciclasine 5, 7-deoxynarciclasine 6, transdihydrolycoricidine 7, 3-epi-trans-dihydrolycoricidine 8, and 3-deoxytrans-dihydrolycoricidine 9.Letter pubs.acs.org/acsmedchemlett
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