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1.
Cell Chem Biol ; 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38917791

ABSTRACT

Molecular glues can induce proximity between a target protein and ubiquitin ligases to induce target degradation, but strategies for their discovery remain limited. We screened 3,200 bioactive small molecules and identified that C646 requires neddylation-dependent protein degradation to induce cytotoxicity. Although the histone acetyltransferase p300 is the canonical target of C646, we provide extensive evidence that C646 directly targets and degrades Exportin-1 (XPO1). Multiple cellular phenotypes induced by C646 were abrogated in cells expressing the known XPO1C528S drug-resistance allele. While XPO1 catalyzes nuclear-to-cytoplasmic transport of many cargo proteins, it also directly binds chromatin. We demonstrate that p300 and XPO1 co-occupy hundreds of chromatin loci. Degrading XPO1 using C646 or the known XPO1 modulator S109 diminishes the chromatin occupancy of both XPO1 and p300, enabling direct targeting of XPO1 to phenocopy p300 inhibition. This work highlights the utility of drug-resistant alleles and further validates XPO1 as a targetable regulator of chromatin state.

2.
Nat Chem Biol ; 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38528120

ABSTRACT

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

3.
RSC Chem Biol ; 3(1): 56-68, 2022 Jan 05.
Article in English | MEDLINE | ID: mdl-35128409

ABSTRACT

While the cholesterol biosynthesis pathway has been extensively studied, recent work has forged new links between inhibition of specific sterol pathway enzymes, accumulation of their unique sterol substrates, and biological areas as diverse as cancer, immunology, and neurodegenerative disease. We recently reported that dozens of small molecules enhance formation of oligodendrocytes, a glial cell type lost in multiple sclerosis, by inhibiting CYP51, Sterol 14-reductase, or EBP and inducing cellular accumulation of their 8,9-unsaturated sterol substrates. Several adjacent pathway enzymes also have 8,9-unsaturated sterol substrates but have not yet been evaluated as potential targets for oligodendrocyte formation or in many other biological contexts, in part due to a lack of available small-molecule probes. Here, we show that genetic suppression of SC4MOL or HSD17B7 increases the formation of oligodendrocytes. Additionally, we have identified and optimized multiple potent new series of SC4MOL and HSD17B7 inhibitors and shown that these small molecules enhance oligodendrocyte formation. SC4MOL inhibitor CW4142 induced accumulation of SC4MOL's sterol substrates in mouse brain and represents an in vivo probe of SC4MOL activity. Mechanistically, the cellular accumulation of these 8,9-unsaturated sterols represents a central driver of enhanced oligodendrocyte formation, as exogenous addition of purified SC4MOL and HSD17B7 substrates but not their 8,9-saturated analogs promotes OPC differentiation. Our work validates SC4MOL and HSD17B7 as novel targets for promoting oligodendrocyte formation, underlines a broad role for 8,9-unsaturated sterols as enhancers of oligodendrocyte formation, and establishes the first high-quality small molecules targeting SC4MOL and HSD17B7 as novel tools for probing diverse areas of biology.

4.
Cell Chem Biol ; 28(6): 866-875.e5, 2021 06 17.
Article in English | MEDLINE | ID: mdl-33636107

ABSTRACT

Small molecules that promote the formation of new myelinating oligodendrocytes from oligodendrocyte progenitor cells (OPCs) are potential therapeutics for demyelinating diseases. We recently established inhibition of specific cholesterol biosynthesis enzymes and resulting accumulation of 8,9-unsaturated sterols as a unifying mechanism through which many such molecules act. To identify more potent sterol enhancers of oligodendrocyte formation, we synthesized a collection of 8,9-unsaturated sterol derivatives and found that 24,25-epoxylanosterol potently promoted oligodendrocyte formation. In OPCs, 24,25-epoxylanosterol was metabolized to 24,25-epoxycholesterol via the epoxycholesterol shunt pathway. Increasing flux through the epoxycholesterol shunt using genetic manipulation or small-molecule inhibition of lanosterol synthase (LSS) increased endogenous 24,25-epoxycholesterol levels and OPC differentiation. Notably, exogenously supplied 24,25-epoxycholesterol promoted oligodendrocyte formation despite lacking an 8,9-unsaturation. This work highlights epoxycholesterol shunt usage, controlled by inhibitors of LSS, as a target to promote oligodendrocyte formation. Additionally, sterols beyond the 8,9-unsaturated sterols, including 24,25-epoxycholesterol, drive oligodendrocyte formation.


Subject(s)
Cholesterol/analogs & derivatives , Intramolecular Transferases/metabolism , Oligodendroglia/metabolism , Animals , Cells, Cultured , Cholesterol/biosynthesis , Cholesterol/chemistry , Male , Mice , Oligodendroglia/cytology
5.
Nat Prod Rep ; 37(9): 1229-1261, 2020 09 23.
Article in English | MEDLINE | ID: mdl-32412021

ABSTRACT

Covering: up to 2019 Selective synthesis with control of remote stereogenic centers has long been a challenge in organic chemistry. In recent years the interest in this topic has been energized by isolation and synthetic studies of tetrafibricin and other natural products containing 1,5-polyols, such as amphidinol 3, marinomycins, and caylobolide. Here we discuss recent developments in 1,5-polyol synthesis, including an overview of selected bioactive natural products in this class and examples of new synthetic methodologies and strategies dedicated to remote stereocontrol in these structures. To illustrate in greater depth, we review several instructive examples of how these innovations have been applied in synthetic studies on tetrafibricin.


Subject(s)
Biological Products/chemistry , Macrolides/chemistry , Polyketides/chemistry , Biological Products/chemical synthesis , Macrolides/chemical synthesis , Molecular Structure , Polyketides/chemical synthesis
6.
J Org Chem ; 83(22): 13650-13669, 2018 11 16.
Article in English | MEDLINE | ID: mdl-30372076

ABSTRACT

Diverse classes of natural products contain chiral 1,5,9- and 1,5,7-triol stereotriads, including the novel fibrinogen receptor antagonist tetrafibricin. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to 1,5-polyol families from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. In the accompanying paper, we present a solution to these problems via an iterative configuration-encoded strategy that exploits Julia-Kocienski couplings of enantiopure α-silyloxy-γ-sulfononitrile building blocks. The stereocontrol is unambiguous, and the building blocks are available in multigram quantities via asymmetric catalysis. This approach efficiently accessed a C26-C40 subunit of tetrafibricin that contains a syn, syn-1,5,9-triol and all of the stereochemistry and functionality needed to advance toward tetrafibricin. A modification afforded the anti, syn-1,5,7-triol within the C15-C25 fragment of tetrafibricin by merging 1,5-polyol synthesis with diastereoselective intramolecular conjugate addition. The union of the C15-C25 and C26-C40 fragments was achieved via a BF3·OEt2-mediated Mukaiyama aldol construction with high 1,3- anti stereoinduction, revealing some unexpected insights on the impact of silyl protecting groups on 1,3- anti diastereocontrol by a ß-siloxyaldehyde aldol acceptor. Directed 1,3- anti reduction completed the stereostructure of the C15-C40 portion of tetrafibricin, with configurations established by a combination of NMR experiments.

7.
J Org Chem ; 83(22): 13636-13649, 2018 11 16.
Article in English | MEDLINE | ID: mdl-30365891

ABSTRACT

Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia-Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia-Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin.

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