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Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) are rare, severe developmental and epileptic encephalopathies with poor prognosis, and novel drugs are urgently needed to meet clinical needs. CYP46A1 (cholesterol 24-hydroxylase, CH24H) is mainly responsible for the metabolism of cholesterol to 24(S)-hydroxycholesterol in the brain and is implicated in many brain disorders through the mediation of excitatory amino acid transporter 2 (EAAT2) and N-methyl-D-aspartate (NMDA) receptors. Inhibition of CYP46A1 is supposed to provide a novel treatment for disorders associated with neural hyperexcitation, such as epilepsy and epileptic syndromes. Soticlestat, a potent CYP46A1 inhibitor being developed by Takeda, is indicated for LGS and DS but suffers from unsatisfactory in vivo potency in animal models and clinical trials. We designed three series of soticlestat derivatives to explore the structure–activity relationship (SAR) with the aim of finding more potent CYP46A1 inhibitors and understanding the SAR of CYP46A1 inhibitors represented by soticlestat. Eventually, three compounds with a benzenesulfonamide moiety (in subseries C-4) that serves as an isostere of OH in soticlestat were discovered with very potent CYP46A1 inhibitory activities comparable to soticlestat, and an interesting flat SAR profile was observed in some subseries. The findings in the present study provide insight into the SAR of CYP46A1 inhibitors and should be valuable for the future design of novel CYP46A1 inhibitors.

Radiotherapy is one of the conventional methods for the treatment of cancers. Boron neutron capture therapy (BNCT) has emerged as a promising and well-recognized modality for treating certain types of cancers. BNCT is a binary radiotherapy that largely depends on neutron beams and 10B carriers. Although an “ideal” boron carrier should fulfill multiple criteria, high tumor/normal tissue ratio (T/N > 5) and high tumor uptake of boron (>20 μg/g) are critically important. First-generation (boric acid and derivatives) and second-generation (BPA and BSH) boron carriers suffer from poor T/N and extremely high dose in clinical use (500 mg/kg and usually >30 g for each patient). Glucose transporter 1 (GLUT1) is overexpressed on the membrane surface of multiple tumors and is a potential target for third-generation boron carrier to achieve high T/N and high tumor uptake of boron. However, the boron-bearing sugar derivatives designed in the last few decades have suffered from suboptimal T/N values and significant cytotoxicity. In the present study, a total of two categories comprising 6 series (28 in total) of boron-bearing sugar derivatives were designed and synthesized and their cellular boron uptake, T/N, and cytotoxicity were evaluated. The structure–activity relationship (SAR) of these target compounds was analyzed, and one of the target compounds, B3, a phenyl C-mannoside with an o-carborane moiety, exhibited the best boron-carrying profile, which featured 10.6-fold higher boron uptake by the SCC-9 cell line and a largely improved T/N (3.3 for B3 vs. 1.4 for BPA) compared with the current clinical gold standard BPA. Therefore, the chemical structure of B3 represents a privileged candidate structure for the future design of “ideal” boron carriers for BNCT.

Sarcasm is a complex emotional expression often marked by semantic contrast and incongruity between textual and visual modalities. In recent years, multi-modal sarcasm detection (MMSD) has emerged as a vital task in affective computing. However, existing models frequently rely on superficial spurious cues—such as emojis or hashtags—during training and inference, limiting their ability to capture deeper semantic inconsistencies and undermining generalization to real-world scenarios. To tackle these challenges, we propose Multi-Modal Mixture-of-Experts (MM-MoE), a novel framework that integrates diverse expert modules through a global dynamic gating mechanism for adaptive cross-modal interaction and selective semantic fusion. This architecture allows for the model to better capture modality-level incongruity. Furthermore, we introduce MMSD3.0 and MMSD4.0, two cross-dataset evaluation benchmarks derived from two open source benchmark datasets, MMSD and MMSD2.0, to assess model robustness under varying distributions of spurious cues. Extensive experiments demonstrate that MM-MoE achieves strong performance and generalization ability, consistently outperforming state-of-the-art baselines when encountering superficial spurious correlations.

Branched-chain amino acid aminotransferases (BCATs), existing as the two isoforms BCAT1 and BCAT2, are responsible for the catabolism of branched-chain amino acids (BCAAs) and are highly upregulated and implicated in a diverse range of cancers. BCAT1 inhibitors represent a potential class of therapeutic agents for cancers; however, none have yet progressed to clinical development. Our earlier research identified WQQ-345 as a novel BCAT1 inhibitor featuring a unique bridged bicyclic skeleton and demonstrating both in vitro and in vivo antitumor activity against tyrosine kinase inhibitor (TKI)-resistant lung cancer with high BCAT1 expression. In the present study, we proceeded to modify the structure of WQQ-345 by two-round structure–activity relationship (SAR) exploration, leading to the discovery of a bicyclo[3.2.1]octene-bearing GABA derivative 7. Compound 7 exhibited a 6-fold enhancement in BCAT1 enzymatic inhibitory activity compared to the parent compound WQQ-345 and could effectively suppress the growth of 67R cells that highly expressed BCAT1 and was resistant to third-generation TKIs. GABA derivatives are an important chemical class of BCAT1 inhibitors, and therefore, the findings in the present study represent great progress both in the discovery of potent BCAT1 inhibitors with new chemical structures and in the treatment of cancer resistance.

Aryl thiols constitute a crucial class of structural motifs and synthetic building blocks, while S‐aryl thiocarboxylates represent an important class of latent aryl thiol precursors. CuI‐catalyzed Ullmann‐type cross coupling of aryl halides and thiobenzoic acid is a widely used synthetic method for S‐aryl thiocarboxylates. Inspired by two individual methods reported earlier and associated drawbacks, a convenient one‐pot two‐step CuI‐catalyzed procedure for the synthesis of S‐(N‐heteroaryl) thiocarboxylates from N‐heteroaryl bromides and thiobenzoic acid was developed by combining of the two reaction systems and subsequent systematic optimization of the reaction conditions. This procedure employed CuI as a transition metal catalyst, a substoichiometric amount of NaI as iodide source and N,N’‐dimethyl‐1,2‐ethanediamine and 1,10‐phenanthroline as two ligands sequentially in each step. This one‐pot procedure is highlighted by shorter reaction time, less iodide source and scalability compared to the two reported procedures while maintaining comparable overall isolated yields. Its utility was demonstrated by providing an alternative synthetic route to 25 and 26, two dual serotonin/dopamine receptor modulators, with fewer reaction steps and avoidance of harsh reaction conditions. A one‐pot two‐step CuI‐catalyzed procedure for the synthesis of S‐(N‐heteroaryl) thiocarboxylates from N‐heteroaryl bromides and thiobenzoic acid was developed, which is highlighted by shorter reaction time, a smaller amount of iodide source and scalability.

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a–1x and 1ha–1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

UHRF1 is a pivotal epigenetic regulator bridging DNA methylation and histone modifications, frequently overexpressed in prostate cancer (PCa). However, no UHRF1-targeted therapeutics have advanced to clinical trials. Here, we report the development of H93, a hybrid small molecule integrating functional groups derived from NSC232003 and vorinostat, respectively. H93 exhibits potent anticancer activity in vitro, correlating with UHRF1 protein abundance, and co-crystallization studies confirm that H93 directly binding to the SRA domain of UHRF1. Intriguingly, H93 promotes UHRF1 dimerization, generating a defined binding pocket that stabilizes compound engagement and enhances druggability of UHRF1 as a non-kinase target. Dimerized UHRF1 adopts a “closed” conformation that disrupts its interaction with DNMT1, impairs DNA methylation maintenance, and reactivates epigenetically silenced tumor suppressor genes. In vivo, H93 demonstrates significant antitumor efficacy. Overall, this study elucidates the structural and mechanistic basis of H93, establishing it as a promising UHRF1-targeted therapy for PCa. UHRF1 is a key epigenetic regulator implicated in prostate cancer, yet no targeted therapies have reached clinical trials. Here, the authors develop H93, a hybrid small molecule that directly binds the UHRF1 SRA domain and unexpectedly promotes its dimerization, and disrupts its interaction with DNMT1, reactivates silenced tumor suppressors, and confers potent antitumor efficacy in prostate cancer.

In order to systematically explore and understand the structure–activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a–1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.

Atropisomerism and restricted amide CO–N bond rotation are commonly encountered structural characteristics in drug discovery and development. Inspired by the unusual NMR spectra of soticlestat ( S-1 ), a CYP46A1 inhibitor currently under development in phase 3 clinical trials, soticlestat and its 14 structurally close analogs were designed, synthesized and studied by variable-temperature 13 C NMR, molecular mechanics, quantum mechanics and HPLC to explore the structural characteristics that affect the restricted bond rotations and the number of stable conformations. It is concluded that there are four stable conformations at room temperature which exist as two diastereomers each as a pair of enantiomers, and the interconversion rates of these conformations are intermediate on the NMR time scale but are inseparable by HPLC, justifying that soticlestat can be developed as a mixture of four rotational isomers.