Xin Hua Liu

Stimulator of interferon genes (STING) is a promising therapeutic target for severe acute pancreatitis (SAP), but effective small-molecule inhibitors remain limited. Here, structure−activity relationship studies identified compound D4 as a potent STING inhibitor with favorable cellular activity and safety. D4 directly engaged STING, inhibited its oligomerization and downstream TBK1/IRF3 signaling, and restored macrophage phagocytosis, autophagic flux, and mitochondrial function while suppressing NOD-like receptor family pyrin domain containing 3(NLRP3)-associated pyroptosis. D4 showed oral exposure with 24.70% bioavailability and no overt toxicity at 1000 mg/kg. In a caerulein/LPS-induced SAP model, D4 markedly reduced pancreatic injury, acinar cell necrosis, inflammatory infiltration, and serum amylase and lipase levels. STING knockdown produced similar protective effects. These findings identify D4 as a promising STING-targeting lead compound for SAP treatment.

FTO has been recognized as a promising therapeutic target for acute myeloid leukemia (AML). However, the development of FTO inhibitors with anti-leukemia effects was still limited. Here, based on reasonable design and SAR, a total of 67 compounds were synthesized, among which compound E6 exhibited the strongest activity (FTO IC50 = 5.3 μM, KD = 3.25 μM). MST, CETSA, and DARTS detection confirmed its binding to FTO target. In addition, compound E6 exhibited good activity against MOLM-13 cells and induced it apoptosis. Mechanistic studies shown that compound E6 increased global m6A levels in AML cells, upregulated the FTO downstream targets ASB2 and RARA, and suppressed c-Myc expression. Importantly, compound E6 exhibited acceptable CYP safety and pharmacokinetic properties, significantly inhibited the growth of MOLM-13 xenograft tumors. These results provided novel chemical scaffold for discovery of FTO inhibitor against leukemia.

Telomerase, responsible for extending telomeres and maintaining the malignant potential of tumors, has long been deemed a promising anticancer target. Nonetheless, because of its complex composition, the discovery of highly efficient telomerase inhibitors is a challenging task. Herein, we identify the blockage of telomerase assembly via targeting TCAB1 as a novel avenue for potent telomerase inhibition. Upon this strategy, (R)-(3,4-dimethoxyphenyl)(3-(3-hydroxypyrrolidin-1-yl)phenyl)methanone (R)-1b (IC50 = 2.04 nM), which directly targets TCAB1 and impairs telomerase assembly via obstructing the TCAB1-hTR interaction, has been discovered. Notably, its binding pocket and the critical residues are confirmed for further drug design. In vivo, (R)-1b remarkably sensitized tumors to small-molecule PD-L1 inhibitors and induced tumor regression, underscoring its potential for augmenting the efficacy of tumor immunotherapy. This study paves the way for the exploration of telomerase inhibitors with a distinctive mechanism of action via targeting TCAB1 and blocking telomerase assembly.

CDK8 exerts important physiological functions, particularly in CRC, by forming intermediate complexes with Cyclic C, MED12, and MED13. In this work, different from the design of traditional single CDK8 protac degraders, a novel potent dual target CDK8 and Cyclic C protac degrader (compound 3) were designed and synthesized. It exhibited the good degradation efficiency against CDK8 ((DC 50 =2.58 μM) and Cyclic C (DC 50 =5.48 μM), along with high selectivity that had no effect on CDK1-7 and CDK9. Importantly, compound 3 could also lower the expression of Cyclin C by reducing mRNA levels, thus better reducing the content of Cyclin C and inhibiting the formation of intermediate complex composed of CDK8, Cyclin C, MED12, and MED13 so that it could better inhibit the biological function of CDK8.Mechanism studies have shown that it had a stronger inhibitory effect on the Wnt/β -catenin signaling pathway and cell cycle regulation than compound C29. This study provides new ideas for the design of CDK8 degrading agents .

SAMHD1 regulates intracellular nucleotide pool composition, and its overexpression is linked to tumor resistance to nucleoside drugs, organ injury, and fibrosis. Existing SAMHD1 inhibitors only exhibit activity in biochemical assays without intracellular effects, rendering it a difficult-to-drug target. Herein, the discovery of NP12, the first SAMHD1 degrader with intracellular activity was reported. The DC₅₀ value of NP12 for SAMHD1 degradation within 48 h was 1.2 μM, and its degradation efficiency D_max reached 89% at 5 μM. NP12 binds to SAMHD1 in cells and mediates SAMHD1 degradation with low off-target effects. In a bleomycin-induced pulmonary fibrosis mouse model, NP12 delayed pulmonary fibrosis progression and exerted a protective effect on lung tissue. Collectively, PROTAC-mediated SAMHD1 degradation represents an effective strategy for regulating intracellular SAMHD1 activity, and NP12 serves as a novel tool to support studies on SAMHD1 biology and the development of targeted drugs for tumor drug resistance and inflammatory diseases.

The breaking of the endocyclic S-aryl bond of strainless thioxanthene derivatives by transition metal-catalyzed ring-opening reactions is still underdeveloped.