Plinabulin, a derivative of phenylahistin, is a microtubule-protein inhibitor that is being studied as a potential antitumor agent. In this study, 33 novel derivatives were designed and synthesized. The results showed th...Plinabulin, a derivative of phenylahistin, is a microtubule-protein inhibitor that is being studied as a potential antitumor agent. In this study, 33 novel derivatives were designed and synthesized. The results showed that most derivatives have significant inhibitory effects on the proliferation of tumor cells at the nanomolar level. Among them, compound showed robust antiproliferative activity against H460 lung cancer cells. Further studies demonstrated that compound not only disrupted the microtubule network and induced G2/M phase arrest but also enhanced p53 protein expression, thereby inhibiting the function of the antiapoptotic BCL-2 protein. This led to mitochondrial dysfunction and a significant increase in reactive oxygen species (ROS) levels in tumor cells, ultimately inducing tumor cell apoptosis. Importantly, compound not only surpassed docetaxel in inhibiting tumor growth in the mouse allograft model using LLC cells but also demonstrated a good safety profile.
Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapeutic options. Mixed lineage kinase 3 (MLK3) plays a key role in TNBC progression. To enhance the therapeutic impact of MLK3 inhibition in TNBC,...Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapeutic options. Mixed lineage kinase 3 (MLK3) plays a key role in TNBC progression. To enhance the therapeutic impact of MLK3 inhibition in TNBC, a novel MLK3 inhibitor scaffold was optimized to incorporate inhibition of NAMPT, often upregulated in TNBC to meet the increased demand for NAD. Cell-free and cell-based assays for MLK3 and NAMPT inhibition drove the design and optimization of , a dual inhibitor with matched nanomolar inhibition for MLK3 and NAMPT, antiproliferative in TNBC cell lines, with acceptable metabolic stability and bioavailability. attenuated tumorigenesis in a syngeneic mouse breast cancer model, increasing apoptosis via inhibition of MLK3 and NAMPT, attenuating macrophage and neutrophil infiltration and increasing tumor T-cell markers without change in B-cell count. These data support the dual inhibition of MLK3/NAMPT as a therapeutic approach to TNBC, with the potential for tumor immuno-sensitization.
cGAS overactivation is linked to various inflammatory and autoimmune diseases. Recent studies identify HDACs as critical regulators of cGAS, suggesting that dual cGAS/HDAC inhibition could be a novel therapeutic strategy...cGAS overactivation is linked to various inflammatory and autoimmune diseases. Recent studies identify HDACs as critical regulators of cGAS, suggesting that dual cGAS/HDAC inhibition could be a novel therapeutic strategy. Herein, we report the identification of an HDAC/cGAS dual inhibitor, containing a hydroxamic acid moiety. This compound exhibited potent inhibitory activity against human and mouse cGAS (IC: 0.17 and 1.80 μM, respectively) and moderate activity against HDAC3 and HDAC6 (IC: 1.2 and 0.4 μM, respectively). Mechanistically, directly suppresses cGAS activity and increases its acetylation levels via HDAC3 inhibition. This dual-action profile resulted in robust therapeutic efficacy in murine models of inflammatory bowel disease and Aicardi-Goutières syndrome. Collectively, represents the first cGAS/HDAC dual inhibitor, offering a promising lead for further investigation into cGAS-dependent disorders.
The oncogenic Y220C mutation destabilizes the p53 DNA-binding domain by creating a druggable surface crevice. Although the clinical advancement of validates this target, the scarcity of structurally distinct correctors...The oncogenic Y220C mutation destabilizes the p53 DNA-binding domain by creating a druggable surface crevice. Although the clinical advancement of validates this target, the scarcity of structurally distinct correctors limits exploration of this chemical space. Using a structure-guided design strategy, we identified as an indole-based p53-Y220C stabilizer that engages the mutation-induced cavity. significantly enhanced the thermodynamic stability of the mutant protein (Δ = +3.7 °C) and restored p53-dependent transcriptional activity, primarily inducing cell cycle arrest rather than acute apoptosis. Despite rapid metabolic clearance and the need for intraperitoneal dosing, achieved 59.2% tumor growth inhibition in a xenograft model. Although further pharmacokinetic optimization is required, serves as an alternative structural template for future medicinal chemistry efforts.
Quinolones substituted at the 2- and 3-positions with biaryl and diphenylether groups have been investigated for their antimalarial potential. ELQ-300, with a 3-position diphenyl ether, is at an advanced stage of preclin...Quinolones substituted at the 2- and 3-positions with biaryl and diphenylether groups have been investigated for their antimalarial potential. ELQ-300, with a 3-position diphenyl ether, is at an advanced stage of preclinical development. Here, we synthesize the 2-position isomer of ELQ-300, i.e., HLQ-102, and describe synthetic procedures for preparing it that avoid the use of expensive catalysts and afford access to substituted quinolones bearing substituents in the 2-position as well as the benzenoid ring and with the critical 3-position CH group. We profile HLQ analogs for their antimalarial activity along with pharmacokinetics of the selected lead molecule. Cross-resistance patterns indicate that, like its predecessor, HLQ-102 targets the Q site of the parasite cytochrome bc complex. This finding suggests the existence of two separate troughs in the target protein capable of accommodating such large structural features regardless of whether it is placed at the 2- or 3-positon of the quinolone ring.
The clinical translation of gold(I) pharmacophores for liver cancer is hindered by rapid deactivation, poor tumor selectivity, and off-target toxicity. To address these limitations, we engineered a tumor-targeting bovine...The clinical translation of gold(I) pharmacophores for liver cancer is hindered by rapid deactivation, poor tumor selectivity, and off-target toxicity. To address these limitations, we engineered a tumor-targeting bovine serum albumin (BSA)-based nanoarchitecture loaded with a gold(I) complex, designated TEP NPs. As an integrated BSA-gold(I) nanoplatform, TEP NPs inherently induce ferritinophagy and leverage the enhanced permeability and retention (EPR) effect and pH-responsive release for TME-triggered gold(I) delivery. TEP NPs inhibit thioredoxin reductase (TrxR), disrupting redox homeostasis and inducing mitochondrial apoptosis. Simultaneously, TEP NPs activate NCOA4-mediated ferritinophagy, leading to ferritin degradation and a surge in labile iron that synergizes with TrxR inhibition to drive ferroptosis. This trimodal cell death triggers immunogenic cell death (ICD) and DAMPs release. In vivo, TEP NPs reprogram the tumor microenvironment by recruiting immune effectors, establishing a closed-loop of tumor killing and immune activation.
B7-H3 (CD276) is an emerging target for cancer theranostics, highlighting the need for imaging probes capable of noninvasively quantifying B7-H3 expression in tumors. Here, we developed three Ga-labeled B7-H3-targeting b...B7-H3 (CD276) is an emerging target for cancer theranostics, highlighting the need for imaging probes capable of noninvasively quantifying B7-H3 expression in tumors. Here, we developed three Ga-labeled B7-H3-targeting bicyclic peptide tracers with different PEG linker lengths. All tracers showed high radiochemical purity (>96%), favorable in vitro stability, and rapid blood clearance. Among them, [Ga]Ga-B7H3-FZ1 exhibited the highest affinity ( = 83.22 nM). Micro-PET/CT imaging demonstrated that tumor uptake of [Ga]Ga-B7H3-FZ1 correlated positively with B7-H3 expression across multiple tumor models. In H1299 tumors. B7-H3 overexpression increased uptake from 1.09 ± 0.18 to 3.50 ± 0.97%ID/g at 30 min postinjection, confirming target specificity. Biosafety studies indicated no obvious toxicity. These results support [Ga]Ga-B7H3-FZ1 as a promising PET tracer for noninvasive B7-H3 imaging.
Phosphoglycerate dehydrogenase (PHGDH), a key regulator in the serine biosynthesis pathway, is aberrantly expressed in various cancers, making it an attractive therapeutic target. In this study, we designed and synthesiz...Phosphoglycerate dehydrogenase (PHGDH), a key regulator in the serine biosynthesis pathway, is aberrantly expressed in various cancers, making it an attractive therapeutic target. In this study, we designed and synthesized a series of PHGDH inhibitors using a structure-based approach. Among these, compounds ( and () exhibited superior enzymatic inhibition with IC values of 0.091 ± 0.013 μM and 0.061 ± 0.004 μM, respectively. Both compounds effectively suppressed de novo serine biosynthesis and showed antitumor activity in PHGDH-overexpressing MDA-MB-468 and PC9 cells. Notably, compounds and also demonstrated antiproliferative effects against erlotinib-resistant PC9 and HCC827 cell lines, exhibiting synergistic effects when combined with erlotinib. Compound showed enhanced antitumor efficacy in erlotinib-resistant PC9 xenograft models in combination with erlotinib. The X-ray crystallographic analysis revealed the binding mode of within the PHGDH active site. These findings provide a foundation for developing PHGDH-targeted anticancer therapies.
Our previous research found that the poor stability of the antimicrobial peptide Feleucin-K3 (FK3) had limited its transition into clinical application. Herein, we developed a series of FK3 derivatives stapled by all-hyd...Our previous research found that the poor stability of the antimicrobial peptide Feleucin-K3 (FK3) had limited its transition into clinical application. Herein, we developed a series of FK3 derivatives stapled by all-hydrocarbon and thioether to enhance the stability and then implemented an amino acid substitution strategy to reduce the hemolytic toxicity. Consequently, after replacing the first phenylalanine of FK3 with alanine and conducting (, + 4) all-hydrocarbon stapling with ()-2-(4-pentenyl) alanine at the 5,9-position, analog S1-1A displayed the highest therapeutic index, high stability, and potent antimicrobial effects against multidrug-resistant (MDR) bacteria as well as antibiofilm properties. A striking finding was that S1-1A exhibited 8-fold greater antimicrobial activity against resistant strains of than vancomycin. The efficacy of S1-1A in vivo was as effective as vancomycin in the skin wound infection model. Overall, stapled peptide S1-1A showed promising potential for being developed into a novel drug for combating MDR bacterial infections.
Mishra A, Yang WB, Liu TS
… +13 more, Thakur A, Grewal AS, Marczyk J, Stelitano G, Sharma R, Rana M, Singh G, Guru SK, Rath G, Chawla S, Liou JP, Pan CH, Nepali K
An integrated transcriptomic and survival analysis led to the identification of SYK and HDAC isoforms as age- and FLT3-dependent prognostic markers in acute myeloid leukemia (AML). Driven by the aforementioned, our resea...An integrated transcriptomic and survival analysis led to the identification of SYK and HDAC isoforms as age- and FLT3-dependent prognostic markers in acute myeloid leukemia (AML). Driven by the aforementioned, our research group employed a classical ligand-based hybrid pharmacophore strategy to furnish dual-target hybrid frameworks. Antitumor profiling culminated in a tractable bifunctional agent (Compound , dual SYK-HDAC inhibitor) endowed with substantial cell growth inhibitory effects against MV4-11 cell lines (AML cell lines harboring FLT3-ITD mutations). Compound downregulated the expression levels of p-SYK and modulated the expression levels of the biomarkers associated with intracellular HDAC inhibition. Transcriptomic profiling revealed significantly suppressed lipid-associated metabolic pathways with Compound treatment. Moreover, Compound demonstrated an impressive pharmacokinetic profile and exerted significant antitumor efficacy in the FLT3-ITD-positive AML xenograft mouse model (). Also, biochemical blood analysis and histopathological studies revealed that Compound demonstrated a good safety profile.
The development of novel antitubercular agents represents a critical strategy against drug-resistant tuberculosis (TB). In this study, we designed and synthesized a series of novel nitroimidazole derivatives from Deleman...The development of novel antitubercular agents represents a critical strategy against drug-resistant tuberculosis (TB). In this study, we designed and synthesized a series of novel nitroimidazole derivatives from Delemanid by introducing an aliphatic spirocyclic moiety. Most compounds demonstrated potent in vitro antitubercular activity with negligible cytotoxicity. Compound exhibited superior activity against Mtb H37Ra over Delamanid (MIC values: 0.2 vs 1.0 ng/mL), and maintained robust efficacy against clinical drug-resistant strains. Importantly, displayed significantly improved solubility, higher permeability in Caco-2 cell and a lower risk of cardiotoxicity. PK studies revealed that absorbed rapidly following oral administration, with drug exposure exhibiting a favorable linear dose-proportional manner, distinct from the nonlinear PK profile of Delamanid. In a mouse model of TB, outperformed Delamanid in terms of in vivo therapeutic efficacy. Collectively, these findings highlight the promising therapeutic potential of , particularly for the treatment of drug-resistant TB.
Pancreatic cancer remains one of the most lethal malignancies with numerous patients harboring KRAS mutations. Herein, we developed a series of furanyl amide-based SHP2 allosteric inhibitors through optimization of our i...Pancreatic cancer remains one of the most lethal malignancies with numerous patients harboring KRAS mutations. Herein, we developed a series of furanyl amide-based SHP2 allosteric inhibitors through optimization of our in-house lead compound . Among them, exhibited the most potent enzymatic inhibitory activity and significantly impaired the proliferation of KRAS-driven pancreatic cancer cells by inducing cell-cycle arrest and apoptosis. Mechanistic studies revealed that suppressed MAPK signaling while triggering compensatory PI3K-AKT activation. Combining with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. Likewise, coadministrating with a PI3K inhibitor BKM-120 improved antiproliferative efficacy by reversing PI3K-AKT feedback activation. In a PANC-1 xenograft model, combination of with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment.
Triple-negative breast cancer (TNBC) remains difficult to treat because durable response is rarely achieved with conventional occupancy-driven inhibition. The central challenge is not simply a lack of actionable targets...Triple-negative breast cancer (TNBC) remains difficult to treat because durable response is rarely achieved with conventional occupancy-driven inhibition. The central challenge is not simply a lack of actionable targets but a mismatch between TNBC's adaptive network biology and the limited depth of reversible node-by-node intervention. In this Perspective, we argue that the key medicinal chemistry question is not only which protein to engage, but which chemical modality best matches a given biological liability. We focus on metabolic coupling, epigenetic scaffold dependence, immune-stromal exclusion, and DNA damage response plasticity and discuss how these vulnerabilities motivate targeted degradation, molecular glues, covalent inhibition, rational polypharmacology, or prodrug design. Across these modalities, ternary-complex productivity, linker topology, warhead presentation, isoform selectivity, exposure control, and postwashout persistence often matter more than potency alone. Biological vulnerability defines the design problem, chemical modality defines the intervention logic, and durable network control defines success.
Dipeptidyl peptidase-4 (DPP-4) is an important aggravating factor in the progression and exacerbation of type 2 diabetes mellitus (T2DM), a condition characterized by diminished insulin responsiveness because it rapidly...Dipeptidyl peptidase-4 (DPP-4) is an important aggravating factor in the progression and exacerbation of type 2 diabetes mellitus (T2DM), a condition characterized by diminished insulin responsiveness because it rapidly degrades glucagon-like peptide-1 (GLP-1) and other peptide with similar physiological function. Although several small-molecule DPP-4 inhibitors have been developed for the clinical management of T2DM, their therapeutic benefits are only moderate, as the fail to achieve for sustained inhibition of DPP-4. Hence, targeted degradation of DPP-4 using proteolysis-targeting chimera (PROTAC) technology offers an alternative strategy for sustained glycemic control in T2DM.
Dissolution-limited absorption remains a major barrier to oral delivery of kinase inhibitors. BMS-135, a potent pan-CK2 inhibitor with robust antitumor efficacy, exhibited poor aqueous solubility (<1 μg/mL) that translat...Dissolution-limited absorption remains a major barrier to oral delivery of kinase inhibitors. BMS-135, a potent pan-CK2 inhibitor with robust antitumor efficacy, exhibited poor aqueous solubility (<1 μg/mL) that translated to low oral bioavailability (rat: <3%) and pronounced nonlinear pharmacokinetics following dose escalation─limitations unresolvable by precipitation-resistant solution formulations alone. To address this, we explored amino acid ester prodrugs designed to enhance intestinal solubility. Structure-property analysis demonstrated that polybasic side chains sustaining protonation at intestinal pH were critical for solubility enhancement. The l-lysine ester prodrug () markedly improved solubility (pH 6.5: >1000 μg/mL) and delivered a 25-fold improvement in systemic exposure ( = 64.6%) with improved dose proportionality. Mechanistic investigation via portal vein cannulation revealed predominant intestinal first-pass bioconversion, explaining the minimal systemic prodrug exposure. These findings position amino acid prodrugs as a practical, low-risk strategy for unlocking oral bioavailability of dissolution-limited kinase inhibitors, offering broad applicability in contemporary drug discovery and development.
Lu X, Tian Z, Li X
… +17 more, Chen X, Tien JC, Yang Y, Yin Y, Li Q, Huang W, Zhou F, Zhang J, Ren X, Liu D, Todd AJ, Li S, Chen Y, Chinnaiyan AM, Chang S, Ding K, Wang Z
Fibroblast growth factor receptors 2 and 3 (FGFR2/3) are attractive therapeutic targets in multiple human cancers. Here, we report the discovery of a series of tricyclic 1-(4-amino-5-ethynyl-8,9-dihydropyrazino[1',2':1,5...Fibroblast growth factor receptors 2 and 3 (FGFR2/3) are attractive therapeutic targets in multiple human cancers. Here, we report the discovery of a series of tricyclic 1-(4-amino-5-ethynyl-8,9-dihydropyrazino[1',2':1,5]pyrrolo[2,3-]pyrimidin-7(6)-yl)prop-2-en-1-one derivatives as novel covalent FGFR2/3 inhibitors through structure-based design and optimization. The lead compound, , potently suppressed FGFR2- or FGFR3-driven Ba/F3 cells (IC = 1.1 nM and 0.20 nM), with reduced activity against Ba/F3-FGFR1 cells (IC = 17.1 nM) and parental Ba/F3 cells (IC > 1000 nM). In a panel of 416 kinases, selectively inhibited FGFR2/3 kinases, including clinically relevant mutants. Covalent modification of FGFR2/3 was confirmed by mass spectrometry and X-ray crystallography. Functionally, selectively suppressed the proliferation of FGFR2-dependent cancer cell lines, dose-dependently inhibited FGFR2 downstream signaling, and induced apoptosis in an FGFR2-dependent manner. Moreover, demonstrated favorable oral bioavailability (56%) in rats and achieved significant tumor growth inhibition in an SNU-16 gastric cancer xenograft model.
Atherosclerosis is now widely recognized as a chronic inflammatory condition driven by the recruitment of leukocytes, with CXCR4 playing a critical role in plaque inflammation and disease progression. In this study, we r...Atherosclerosis is now widely recognized as a chronic inflammatory condition driven by the recruitment of leukocytes, with CXCR4 playing a critical role in plaque inflammation and disease progression. In this study, we report the development and initial assessment of five novel Ga-labeled small-molecule CXCR4 radiotracers ([Ga]Ga-SDNUM08-12), engineered on an aniline-benzylamine scaffold with varying PEG linker lengths (PEG1 PEG2) and bridging amino acids (glutamic aspartic acid). Notably, [Ga]Ga-SDNUM11, incorporating dual PEG2 units and glutamic acid, exhibited optimal hydrophilicity, rapid blood clearance, excellent stability and high binding affinity. In a turpentine-induced sterile muscle inflammation mouse model, [Ga]Ga-SDNUM11 emerged as the lead radiotracer with optimal imaging efficacy. Subsequently, in a rat common carotid artery (CCA) atherosclerosis model, it exhibited focal uptake colocalizing with CXCR4-positive plaques. These findings establish [Ga]Ga-SDNUM11 as a promising CXCR4-targeted radiotracer for PET imaging of atherosclerotic plaque inflammation and cardiovascular risk stratification.
Exapicheidou I, Tsarenko A, Zeller L
… +13 more, Ibrahim H, Baumann C, Shams A, Hoffmann PA, Li Y, Kany AM, Hermann J, Slotboom DJ, Müller R, Volkamer A, Hamed MM, Diamanti E, Hirsch AKH
Multiparameter optimization of a previously identified class of inhibitors of the energy-coupling factor (ECF) transporters enabled the confirmation of efficacy. ECFs are a class of transmembrane proteins that play a vi...Multiparameter optimization of a previously identified class of inhibitors of the energy-coupling factor (ECF) transporters enabled the confirmation of efficacy. ECFs are a class of transmembrane proteins that play a vital role in the active translocation of essential nutrients across cell membranes and are therefore important in the fight against antimicrobial resistance. Aiming to improve the drug-like properties of our inhibitory class, we performed a focused structure-activity relationship study around the Eastern part of our starting molecule by exploiting click chemistry. Our multiparameter optimization resulted in compounds with enhanced metabolic stability and solubility, potent activity against both a panel of Gram-positive bacteria, and against the ECF transporters. We further demonstrate rapid bacterial killing using as a model organism and confirmed efficacy of the best compounds in larvae and (zebrafish) infection models, highlighting the therapeutic potential of our approach.