Abstract Purpose: Enzymatic pockets, such as those found in histone deacetylases (HDACs), have long served as attractive targets for drug discovery. However, conventional HDAC inhibitors often lack selectivity and cause systemic toxicity due to paralog redundancy and their incorporation into multi-subunit transcriptional regulatory complexes. To identify more selective modulators, we performed an unbiased yeast genetic screen of ∼52,000 compounds by interrogating the activity of the conserved HDAC/Rpd3L complex. Follow-up mechanistic studies uncovered hits that do not directly inhibit HDAC catalytic activity but instead modulate repression through alternative mechanisms. We subsequently evaluated the lead compound, E6R, in human neuroblastoma cells and mouse xenografts, benchmarking against the enzymatic inhibitor TSA in vitro and Vorinostat (SAHA) in vivo. These studies demonstrate that E6R, a first-in-class non-enzymatic SIN3-HDAC modulator, achieves comparable anti-tumor efficacy with far greater selectivity and minimal global transcriptional disruption. Methods: E6R was evaluated in yeast and SK-N-BE(2)-C neuroblastoma cells using bulk and single-cell RNA-seq (Seq-Well S3), SIN3A ChIP-seq, viability and invasion assays, and mouse xenografts. Results: In yeast, E6R disrupts Sin3/Rpd3L-dependent transcriptional repression without inhibiting HDAC catalytic activity. In human neuroblastoma cells, E6R produced anti-tumor activity comparable to TSA. Transcriptomically, E6R modulated ∼14-fold fewer genes than TSA and caused minimal global perturbation. Interestingly, E6R selectively activated stress- and senescence-associated programs governed by the ATF4-driven integrated stress response (ISR), including GDF15, DDIT3, ATF3, and FGF21, while inducing minimal off-target effects. SIN3A ChIP-seq revealed promoter-proximal loss of SIN3A binding at several ISR loci, most notably GDF15 (∼55 bp upstream of the TSS), consistent with direct de-repression through dissociation of the SIN3-HDAC complex. Although both compounds shared repression of E2F, MYC, and glycolytic targets and activation of p53, TNFα/NF-κB, and apoptotic signaling, E6R induced a distinct stress-adaptive state through an HDAC-independent mechanism. Functionally, E6R significantly reduced neuroblastoma cell invasion and tumor growth with limited cytotoxicity. In vivo, E6R inhibited neuroblastoma xenograft growth comparably to Vorinostat, supporting non-enzymatic HDAC modulation as a therapeutic alternative. Conclusions: Together, these data strongly suggest that E6R is a selective, non-enzymatic SIN3-HDAC modulator that reprograms chromatin from a repressive to a stress-adaptive, anti-proliferative state, offering a mechanistically distinct and potentially safer framework for HDAC-targeted cancer therapy. Citation Format: Olivia Debnath, Julien Olivet, Soon Gang Choi, Yasmine Bramerloo, Jeremy Blavier, TINA O'GRADY, Florent Laval, Vladimir V. Botchkarev, Bin Hu, Anthony C. Varca, Jonathan Bruyr, Samira Ibrahim, Tasneem Jivanjee, Joshua D. Bromley, Sarah K. Nyquist, Natalia Calonghi, Alessandra Stefan, Alejandro Hochkoeppler, Maria Francesca Baietti, Eleonora Leucci, Michael A. Calderwood, Tong Hao, Alex K. Shalek, David E. Hill, Sara J. Buhrlage, Sirano Dhe-Paganon, Franck Dequiedt, Jean Claude Twizere, Marc Vidal. Targeting non-enzymatic HDAC-mediated repression reveals a selective stress-adaptive mechanism for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6776.

Deubiquitinating enzymes (DUBs) are crucial regulators of ubiquitin signaling and protein degradation that remain incompletely understood in part due to the lack of high-quality chemical probes. To address this challenge, we developed CAS-010, a low nanomolar, ubiquitin-competitive inhibitor of USP28 that demonstrates preferential activity against USP28 over other DUBs, while also exhibiting some activity against the closely related USP25. We rationalized our SAR trends and observed selectivity using a crystal structure of USP28 in complex with an inhibitor. We validated on-target effects of CAS-010 on the negative regulation of p53 transactivation in the wild-type setting. We demonstrated that CAS-010 disrupts the 53BP1-USP28 interaction, and more broadly showed that USP28 catalytic activity contributes to this key interaction. Taken together, CAS-010 and the accompanying negative control compound WPT-086 and inhibitor-resistant mutant provide well-validated tools for further characterizing the role of USP28 in p53-mediated effect on cell cycle control and cell fate.

Catalytic asymmetric cross-coupling of imines constitutes a particularly desirable method for the synthesis of chiral vicinal diamines directly from readily available achiral precursors. The potential of this method lies in the possibility of utilizing a variety of imines as reacting partners. However, the realization of highly stereoselective cross-coupling of two different imines proved to be a formidable challenge. Herein we report an unprecedented catalytic asymmetric cross-coupling reaction that tolerates a variety of ketimines and aldimines as nucleophiles and electrophiles, respectively. The realization of this reaction resulted from the development of a new chiral ammonium catalyst, which was guided by insights from studies of catalyst-substrate interactions. With a 0.5 mol % loading of an organocatalyst, this reaction proceeded in a highly diastereo- and enantioselective manner to afford a diverse range of chiral vicinal diamines as nearly single stereoisomers. This catalytic reaction establishes a new approach for the asymmetric synthesis of chiral vicinal diamines.

Deubiquitinating enzymes (DUBs) are an emerging drug target class of ~100 proteases that cleave ubiquitin from protein substrates to regulate many cellular processes. A lack of selective chemical probes impedes pharmacologic interrogation of this important gene family. DUBs engage their cognate ligands through a myriad of interactions. We embrace this structural complexity to tailor a chemical diversification strategy for a DUB-focused covalent library. Pairing our library with activity-based protein profiling as a high-density primary screen, we identify selective hits against 23 endogenous DUBs spanning four subfamilies. Optimization of an azetidine hit yields a probe for the understudied DUB VCPIP1 with nanomolar potency and in-family selectivity. Our success in identifying good chemical starting points as well as structure-activity relationships across the gene family from a modest but purpose-build library challenges current paradigms that emphasize ultrahigh throughput in vitro or virtual screens against an ever-increasing scope of chemical space.

ABSTRACT Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of an HDAC2 knockout in vivo . We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators. GRAPHICAL ABSTRACT

Deubiquitinating enzymes (DUBs) are a class of isopeptidases that regulate ubiquitin dynamics through catalytic cleavage of ubiquitin from protein substrates and ubiquitin precursors. Despite growing interest in DUB biological function and potential as therapeutic targets, few selective small-molecule inhibitors and no approved drugs currently exist. To identify chemical scaffolds targeting specific DUBs and establish a broader framework for future inhibitor development across the gene family, we performed high-throughput screening of a chemically diverse small-molecule library against eight different DUBs, spanning three well-characterized DUB families. Promising hit compounds were validated in a series of counter-screens and orthogonal assays, as well as further assessed for selectivity across expanded panels of DUBs. Through these efforts, we have identified multiple highly selective DUB inhibitors and developed a roadmap for rapidly identifying and validating selective inhibitors of related enzymes.

Mutations in the Janus Kinase 2 (JAK2) gene resulting in constitutive kinase activation represent the most common genetic event in myeloproliferative neoplasms (MPN), a group of diseases involving overproduction of one or more kinds of blood cells, including red cells, white cells, and platelets. JAK2 kinase inhibitors, such as ruxolitinib, provide clinical benefit, but inhibition of wild-type (wt) JAK2 limits their clinical utility due to toxicity to normal cells, and small molecule inhibition of mutated JAK2 kinase activity can lead to drug resistance. Here, we present a strategy to target mutated JAK2 for degradation, using the cell's intracellular degradation machinery, while sparing non-mutated JAK2. We employed a chemical genetics screen, followed by extensive selectivity profiling and genetic studies, to identify the deubiquitinase (DUB), JOSD1, as a novel regulator of mutant JAK2. JOSD1 interacts with and stabilizes JAK2-V617F, and inactivation of the DUB leads to JAK2-V617F protein degradation by increasing its ubiquitination levels, thereby shortening its protein half-life. Moreover, targeting of JOSD1 leads to the death of JAK2-V617F-positive primary acute myeloid leukemia (AML) cells. These studies provide a novel therapeutic approach to achieving selective targeting of mutated JAK2 signaling in MPN.

•Neuropilins (NRP) have been identified as essential coreceptors for vascular endothelial growth factors (VEGF).•VEGF-NRP interactions exert multifaceted effects on tumor biology.•Structural basis and characteristics of VEGF-NRP interactions guide antagonist design.•Various peptide-based and small molecular NRP antagonists are introduced in detail.

Enabled by the discovery of new cinchonium salts and coadditives, a direct and efficient asymmetric access to trifluoromethylated γ-amino esters/lactones has been realized through the enantioselective and diastereoselective umpolung reaction of trifluoromethyl imines with acrylates or α,β-unsaturated lactones as carbon electrophiles. At 0.5-5.0 mol % catalyst loadings, the newly developed catalytic system activates a variety of imine substrates as unconventional nucleophiles to mediate highly chemo-, regio-, diastereo-, and enantioselective C-C bond forming reactions. The developed synthetic protocol represents an excellent strategy to target a series of versatile and enantiomerically enriched γ-amino esters/lactones in good to excellent yields from the readily available starting materials. Additionally, we found that the epi-vinyl catalysts based on cinchonidine and quinine promote a similarly high enantioselective reaction generating the opposite configuration of chiral products in a highly efficient manner, which allows convenient access to either the R- or S-enantiomer of the chiral amine products in high yields and excellent enantioselectivities.

Cinchona alkaloid-derived chiral catalysts represent one of the most widely applied classes of organocatalysts, which have been successfully utilized in the promotion of a wide variety of asymmetric reactions. Cinchona alkaloids exist in nature as pseudoenantiomers, which allow cinchona alkaloid-catalyzed reactions to provide high enantioselectivities and yields toward both enantiomers of interest in many reactions. On the other hand, the subtle structural difference between pseudoenantiomeric cinchona alkaloids could also lead to uneven efficiency that severely limits the applicability of some cinchona alkaloid-catalyzed reactions. We describe here the elucidation of the origin of and the consequent development of novel modified cinchona alkaloids to address such a problem in asymmetric imine umpolung reactions by cinchonium salts.

This paper describes the mechanistic insight-guided development of a catalyst system, employing a phenolic proton donor catalyst in addition to a cinchonium-derived phase-transfer catalyst, to control the chemoselectivity of two distinct intermediates, thereby enabling the desired asymmetric tandem conjugate addition-protonation pathway to dominate over a number of side-reaction pathways to provide a synthetic approach for the direct generation of optically active amines bearing two nonadjacent stereocenters.

Novel cinchona alkaloid derived chiral phase-transfer catalysts enabled the highly chemo-, regio-, diastereo-, and enantioselective umpolung addition of trifluoromethyl imines to α,β-unsaturated N-acyl pyrroles. With a catalyst loading ranging from 0.2 to 5.0 mol %, this new catalytic asymmetric transformation provides facile and high-yielding access to highly enantiomerically enriched chiral trifluoromethylated γ-amino acids and γ-lactams.

Hypoxia under the tumor microenvironment often causes tumors to be resistant to radiation and chemotherapy.Hypoxia-activated prodrugs(HAPs),which were nontoxic or low-toxic to normal organisms,while they were active to tumor cells after reaching hypoxia microenvironment,have already become a hot spot of antitumor drugs development.The recent progress in the study on HAPs,including N-oxides,quinones,nitro compounds and metal complexes,was reviewed in this paper.

Some chlorinated aromatic compounds, including indole, benzofuran, carbazole, pyridine and aniline derivatives, are difficult to obtain through convenient chlorination. We herein report their efficient synthesis through chlorination with N-chlorosuccinimide (NCS). Optimization of the reaction conditions, including the temperature and the choice of solvent, was also investigated. This approach, which is characterized by a facile procedure, comparatively high yields and environmentally friendly features, provides a straightforward and inexpensive route to several chlorinated aromatic compounds.

A scale-up synthesis of antidepressant drug vilazodone was accomplished in five steps. Friedel–Crafts acylation of 1-tosyl-1H-indole-5-carbonitrile with 4-chlorobutyryl chloride, selective deoxygenation in NaBH4/CF3COOH system coupled with ethyl 5-(piperazin-1-yl)-benzofuran-2-carboxylate hydrochloride, one-step deprotection and esterolysis, and the final ammonolysis led to the target molecule vilazodone in 52.4% overall yield and 99.7% purity. This convenient and economical procedure is remarkably applicable for scale-up production.

The motif of and runs through all of the Shen Congwen's love stories.Shen Congwen usually said is adjacent with death.Love and death in his love narration is linked and Showing a complex multi-form.The reason why Shen Congwen is keen on the motif of and is closely related to the legend of his early experience,the impact of Freud's psychoanalytic and the cultural customs of Western Hunan etc.

Secondary and tertiary allylic alcohols undergo 1,3-isomerization smoothly in the presence of methanesulfonic acid under simple and efficient conditions to afford selectively the corresponding primary E-allylic alcohols in excellent yields.

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The diastereoselective addition of organometallic reagents to chiral sulfinimines is a well-known method for generating new stereocenters, and examples of addition of unsubstituted allylmagnesium reagents are abundant. In this work the authors report the efficient asymmetric addition of substituted racemic allylzinc reagents to Ellman’s imine (1). Formation of homoallylic amines bearing two new stereocenters in excellent yield and diastereoselectivity is described.