The efficacy of FLT3 inhibitors in acute myeloid leukemia (AML) is severely limited by resistance mutations, particularly the recalcitrant gatekeeper F691L and activation loop D835V/Y variants. Herein, through the structure-guided optimization of our previously reported lead SILA-123, we identified FYJ-195, a highly potent type II FLT3 inhibitor capable of overcoming these recalcitrant mutants. FYJ-195 exhibited single-digit nanomolar potency against Ba/F3-FLT3-ITD-F691L (IC50 = 9.09 nM) and subnanomolar activity against Ba/F3-FLT3-ITD-D835Y (IC50 = 4.64 nM) and Ba/F3-FLT3-ITD-D835V (IC50 = 0.76 nM). In vivo, FYJ-195 induced profound tumor regression (TGI = 125%) in the MV4-11 xenograft model (10 mg/kg) and achieved robust tumor growth suppression (TGI = 68.6%) in the Ba/F3-FLT3-ITD-F691L model (50 mg/kg), where quizartinib was ineffective. Mechanistic studies confirmed that FYJ-195 effectively blocked FLT3 signaling and induced apoptosis without observable toxicity. Collectively, FYJ-195 represents a promising lead candidate for drug-resistant AML.

Wee kinases, including Wee1, Myt1 (PKMYT1) and Wee2, serve as critical regulators of the DNA damage response by inhibiting the G2/M transition and have attracted increasing attention as a targetable vulnerability in TP53-deficient cancers. Wee1 is the fastest progressing member in clinical research, and its inhibitors such as AZD-1775 and ZN-c3 are under clinical evaluation. Because toxicity and resistance persist with existing agents, research is moving toward newer strategies such as protein degradation technologies. Proceeding from sequence and structure, we, for the first time, use chemoinformatics to delineate the chemical space of the Wee1 binding pocket and classify reported inhibitors into three pocket engagement types, thereby constructing a high-resolution pocket map and an anchorable Markush for designing inhibitors with high selectivity and activity. We further summarize design principles for targeted degradation of Wee1 and outline combination strategies grounded in synthetic lethality, and we curate recent preclinical and ongoing clinical advances with discussion of biomarker-guided enrollment and dosing schedules. By linking structural mechanisms to pharmacology and clinical placement, this review provides an actionable framework for next-generation Wee1-directed drug design and translation in oncology.

Two series of bufalin derivatives including three compounds were designed, synthesized, and evaluated for their antiproliferative activity against A549 (non-small cell lung cancer) and HeLa (cervical cancer) cells. Structure-activity relationship (SAR) analysis revealed that methylation of the C3β-hydroxy group or replacement of the C17 six-membered unsaturated lactone ring with a five-membered lactone ring reduced the antitumor activity. These findings indicate that both the C3β-OH group and the intact C17 lactone moiety are essential pharmacophoric elements for the antitumor activity of bufalin.

FLT3 is a validated therapeutic target in acute myeloid leukemia (AML), yet resistance mutations frequently limit current inhibitors. Here, we report a series of 6-methylisoxazolo[5,4-b]pyridin-3-amines that covalently target Cys807, a previously unexploited nucleophilic residue within the FLT3 kinase domain. Compound 18 (FLC-8) potently inhibited FLT3-WT (IC50 = 10.2 nM) and clinically relevant mutants G697R (IC50 = 11.6 nM) and N676D (IC50 = 24.1 nM). Covalent engagement of Cys807 was confirmed by mass spectrometry, peptide mapping, and loss of activity upon C807S mutation. FLC-8 suppressed FLT3-mediated STAT5, AKT, and ERK signaling and induced apoptosis in AML cells while maintaining low-nanomolar potency over 72 h. Kinome profiling revealed a narrow inhibition spectrum. In vivo, FLC-8 inhibited MV4-11 xenograft growth (TGI: 136-178% at 10-50 mg/kg) without overt toxicity. These findings identify Cys807 as a covalent binding hotspot in FLT3 and establish FLC-8 as a promising scaffold for next-generation FLT3 inhibitor development.

Macrophage membrane-camouflaged nanoparticles (MmNPs) are emerging as efficient nanoplatforms for targeted delivery to inflammatory sites, tumors, and infected tissues due to the innate characteristics of macrophages. This biomimetic strategy effectively addresses several limitations of traditional targeted drug delivery systems, offering improved biocompatibility, extended blood circulation, immune evasion, and site-specific homing. Compared to conventional functionalization methods, MmNPs provide a simplified method for creating multifunctional nanoparticles. In this review, we explore the origins and functions of macrophages, highlighting how MmNP platforms are leveraged for precise drug delivery. The latest applications of MmNPs in targeted delivery are summarized, focusing on their intrinsic targeting properties, membrane surface modifications and designs for environmental stimulus response. Finally, we discuss the prospects and challenges in translating MmNP technology from experimental settings to clinical applications, aiming to inspire continued innovation in the design of MmNP for precise and effective drug delivery strategies against complex diseases.

RET fusions and activating mutations drive multiple human cancers, while resistance mutations limit the efficacy of current selective RET inhibitors. Here, we report CN-3, a potent RET inhibitor active against clinically relevant mutants, including solvent-front (G810R/S/C), gatekeeper (V804M), hinge (Y806H), and catalytic loop (M918T) variants. CN-3 inhibited all tested RET mutants (IC50 < 5 nM) and selectively suppressed proliferation of RET-driven cellular models, including TT (IC50 = 2.48 ± 0.78 nM) and LC-2/ad (IC50 = 17.05 ± 4.90 nM) cells, as well as Ba/F3 cells expressing RET fusions or mutations, without affecting RET-independent or normal cells. Mechanistically, CN-3 blocked RET autophosphorylation and downstream SHC/AKT/ERK signaling, inducing G0-G1 arrest and apoptosis. In RET-driven xenografts, CN-3 showed dose-dependent antitumor efficacy with good tolerability. Kinase profiling revealed moderate selectivity, with off-target activity mainly restricted to a limited group of receptor tyrosine kinases. These results support CN-3 as a promising lead for next-generation RET-targeted therapies.

Retinoic acid receptor-related orphan receptor γ (RORγ) is a key transcriptional regulator of the T helper 17 cell and has emerged as a promising therapeutic target for autoimmune diseases. To identify novel orthosteric inhibitors of RORγ, we designed and synthesized ten fluorescent probes targeting the RORγ orthosteric site. Among them, probe 19g exhibited the best performance (Kd = 252 nM, fluorescence quantum yield = 29.7%) and was subsequently employed to establish a fluorescence polarization (FP)-based assay for screening natural orthosteric binders. Using this optimized FP system, the natural polyphenolic compounds tannic acid (FP Ki = 250 ± 13 nM) and epigallocatechin gallate (EGCG, FP Ki = 506 ± 8 nM) were identified as RORγ ligands. Both compounds exhibited significant inhibitory activity against RORγ, as assessed by RORγ-Gal4 reporter, qPCR and CESTA assays. Furthermore, in the psoriatic-like mouse model, EGCG can effectively alleviate psoriatic-like skin lesions. Collectively, the fluorescent probes and FP-based screening platform provide convenient tools for the discovery and mechanistic investigation of RORγ orthosteric inhibitors. Moreover, the identification of RORγ as a molecular target of tannic acid and EGCG offers new insights into the anti-inflammatory mechanisms of these natural compounds.

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

Mucosa-associated lymphoid tissue protein 1 (MALT1), a cysteine protease and the sole paracaspase in humans, plays a pivotal role in the survival and proliferation of NF-κB-dependent malignant cancers, particularly MALT lymphoma and diffuse large B-cell lymphoma (DLBCL). Dysregulated MALT1 activity is implicated in various malignancies, highlighting its importance as a therapeutic target. This Perspective provides an overview of MALT1's structural and functional characteristics, summarizes recent advancements in small-molecule inhibitors and degraders targeting this protein, and discusses compound structures, structure-activity relationship (SAR) analyses, and biological activities. We aim to inform future research efforts to enhance the activity, selectivity, and pharmacological properties of MALT1-targeting compounds, establishing a foundational framework for drug development in this critical area of cancer therapy.

A series of novel C-28 amino acid/amide conjugates and oligo(ethylene glycol)-modified C-2, C-3 pyrazole-fused betulinic acid derivatives were designed, synthesized, and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these, compound 18, bearing a C-28 oligo(ethylene glycol) amino amide ester linkage, exhibited the most potent inhibitory activity. It demonstrated an IC50 of 7.96 nM against RANKL-induced osteoclastogenesis in RAW264.7 cells, representing a 10-fold increase in potency compared to the XJ13 (IC50 = 0.08 μM) and achieved >50 % inhibition at 0.01 μM. Importantly, the inhibitory effects of these compounds on RANKL-induced osteoclast differentiation were not attributed to cytotoxicity, as evidenced by the minimal cytotoxicity of compound 18 at 10 μM. Mechanistic studies showed that compound 18 could dose-dependently suppress the expression of osteoclast marker genes (TRAP, CTSK) and proteins (c-Fos, MMP-9). Furthermore, in an ovariectomized (OVX) mouse model, compound 18 (10 and 20 mg/kg, intraperitoneally, i.p.) dose - dependently prevented bone loss by improving key micro-CT parameters and decreasing serum bone resorption markers (CTx). Overall, compound 18 emerged as a highly promising candidate for the treatment of RANKL-driven osteoporosis.

The total synthesis of bufotalin was completed in a novel method from the starting material androstenedione (11). Essential to the synthesis was the implementation of Shibuya oxidation for the construction of C14-/3-OH. The double bond in the D-ring is completed by the selective substitution of bromine at C16 and then elimination. This strategy avoids the use of precious metals, greatly reduces the synthesis cost and could be extended to the total synthesis of related natural products.

This study presents an innovative computational method, combined with experimental validation, to predict and elucidate the metabolic pathways of SILA-123, a novel FLT3 inhibitor. Using UFLC/Q-TOF MS, we identified 21 metabolites generated through key reactions (oxidation, reduction, hydrolysis, cleavage, deamination, and glucuronidation). Advanced computational techniques were applied to identify key metabolic enzymes, with results confirmed experimentally. Our findings represent a significant advancement in the field of metabolic prediction. By integrating computational methods with experimental data, we have established a robust framework that can be applied to other therapeutic compounds. This approach not only enhances our understanding of SILA-123's metabolic pathways but also provides a novel strategy for guiding metabolic prediction.

Danatinib, a brand-new compound synthesized in our laboratory for the treatment of acute myeloid leukemia (AML), demonstrates remarkable antitumor activity. However, the pharmacokinetic profile of Danatinib in mice was short with its half-life was only 0.476 h. To address this issue and optimize its therapeutic efficacy, this study investigated the metabolic profiles of Danatinib in mice, both in vitro and in vivo, using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) technology. In the in vitro study, Danatinib was analyzed using mouse liver microsomes, resulting in the identification of eight metabolites. In the in vivo study, Danatinib was administered orally to mice at 20 mg/kg; the samples of plasma, bile, feces, and urine were collected and analyzed, leading to the identification of 34 metabolites. The results showed that those metabolites were formed through various metabolic reactions including hydroxylation, carboxylation, acetylation, hydrogenation, and glucuronidation. This study provides a systematic investigation of the metabolism of Danatinib, offering valuable information for further structural modification to improve its pharmacokinetic profiles.

One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.

The journal retracts the article titled “A Ferulic Acid Derivative FXS-3 Inhibits Proliferation and Metastasis of Human Lung Cancer A549 Cells via Positive JNK Signaling Pathway and Negative ERK/p38, AKT/mTOR and MEK/ERK Signaling Pathways” [...]

A concise and scalable semi-synthesis of (+)-digitoxigenin ( 1 ) has been accomplished in nine linear steps. This route features the construction of the C(15)=C(16) double bond in intermediate 6 via selective C16 bromination followed by elimination. Subsequesntly, a single-step SeO2 oxidation directly installed the C14-beta-hydroxyl group, producing 7 . This strategy avoids precious metals, greatly reduces synthesis costs, and can be extended to the synthesis of related cardiotonic steroids.

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and evaluated several novel ERα-PROTAC agents. After systematic structural optimization, compound A16 was found to have excellent antiproliferative and ERα-inhibitory activities in the breast cancer cell line MCF-7. A16 selectively degraded ERα (DC50 = 3.78 nM) through the ubiquitin-proteasome pathway in a time- and concentration-dependent manner. It effectively attenuated drug resistance (MCF-7 Y537S cells; IC50 = 1.3 nM), inhibited proliferation, and induced apoptosis in MCF-7 cells. In addition, it exhibited excellent antitumor effects (10 mg/kg/d intraperitoneal injection; total growth inhibition = 80.11 %) and a good safety profile in an MCF-7 xenograft model, highlighting its potential as a novel drug candidate for breast cancer.

Background: Alzheimer's disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of beta-amyloid (A beta) is considered the main pathogenies of AD, and beta-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of A beta. Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenyl-benzimidazole derivatives were designed and synthesized in this work. Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1 similar to T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized. Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC50 = 0.45 mu M), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93. Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.