Bioorthogonal bond cleavage reactions that exhibit rapid kinetics in both the initial click and subsequent release steps are essential for applications. In this study, we focus on the bioorthogonal decaging reaction bet...Bioorthogonal bond cleavage reactions that exhibit rapid kinetics in both the initial click and subsequent release steps are essential for applications. In this study, we focus on the bioorthogonal decaging reaction between an -oxide and silylborane, and systematically modify the structure of an -oxide-masked ethylenediamine linker, which undergoes cyclization to release the attached payload upon silylborane activation. Our results uncovered significant structure-cyclization kinetics relationships, leading to the identification of several novel linkers that combine favorable stability with rapid cyclization kinetics ( on the scale of minutes) following activation. Using one representative linker, we constructed a bioorthogonal prodrug of CA-4 that displayed potent antitumor activity only in combination with silylborane both and . We anticipate that these ethylenediamine linkers will have potential application in the design of prodrugs.
Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes o...Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes or as stimulators of oxidative stress, exerting deleterious effects on physiological functions. The hybrid molecule MC1 is designed by integrating melatonin and catechol moieties to reconstruct mitochondrial dynamics and selectively regulate the generation of ROS. MC1 combats cell senescence under oxidative stress and DNA damage, and reprograms the mitochondrial energy metabolism by inhibiting the tricarboxylic acid cycle and glycolysis, while initiating fatty acid oxidation to increase energy production. More importantly, MC1 significantly extends the lifespan of , accompanied by an improvement in muscle strength and physiological functions. The lifespan-extending effect of MC1 arises from its intervention in mitochondrial membrane fusion, the electron transport chain, and differential modulation of ROS. Regulating mitochondrial dynamics and ROS production shows great potential for longevity extension.
STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 lig...STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC = 4 nM and of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC = 5-11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.
Despite the identification of over 600 E3 ligases, current proteolysis-targeting chimeras (PROTACs) predominantly rely on CRBN and VHL. Recently, GID4, a substrate receptor of the CTLH E3 ligase complex, emerged as a pro...Despite the identification of over 600 E3 ligases, current proteolysis-targeting chimeras (PROTACs) predominantly rely on CRBN and VHL. Recently, GID4, a substrate receptor of the CTLH E3 ligase complex, emerged as a promising alternative handle. Herein, through structural simplification of a known GID4 ligand, we developed compound as a potent GID4-recruiting BRD4 degrader. Compound induced efficient, selective, and GID4-dependent BRD4 degradation via the ubiquitin-proteasome pathway (DC = 0.21 ± 0.04 μM). Crucially, maintained degradation activity in VHL- and CRBN-deficient models, exhibiting superior antiproliferative effects in VHL-deficient 786-O renal cell carcinoma (RCC) cells. , achieved significant tumor growth inhibition (TGI = 67%) in a 786-O xenograft model, outperforming corresponding CRBN- and VHL-recruiting analogs. This platform's broader utility was further confirmed by successfully degrading VEGFR2. Overall, this study establishes GID4 as a viable PROTAC handle with therapeutic potential in renal cancer.
Prostate-Specific Membrane Antigen (PSMA) is overexpressed in some prostate cancers and is a viable candidate for targeted radionuclide therapy. PSMA targeted delivery of α particle-emitting actinium-225 to tumors is a p...Prostate-Specific Membrane Antigen (PSMA) is overexpressed in some prostate cancers and is a viable candidate for targeted radionuclide therapy. PSMA targeted delivery of α particle-emitting actinium-225 to tumors is a potential therapeutic option for prostate cancer. A substituted diazacrown ether macrocycle (Macropa) forms stable complexes with [Ac]Ac. In this work, two PSMA-targeting lysine-ureido-glutamic acid pharmacophores are attached to a single Macropa macrocycle to give MacropaBisPSMA. The new conjugate was radiolabeled with [Ac]Ac to give [Ac]AcMacropaBisPSMA. The therapeutic activity of [Ac]AcMacropaBisPSMA was evaluated in mice bearing PSMA-positive PC3-PIP tumor xenografts. [Ac]AcMacropaBisPSMA showed a high degree of tumor uptake and retention at 24 h post injection (23.0 ± 5.4%IA g). Untreated mice in this model had a median survival of 14.5 days. Mice treated with [Ac]AcMacropaBisPSMA (15 kBq) had a median survival of 87 days, and all mice treated with 37 kBq of [Ac]AcMacropaBisPSMA survived the duration of the 90-day study.
The epithelial-to-mesenchymal transition (EMT) and immunosuppressive tumor microenvironment (TME) are key drivers of tumor metastasis. Here, a series of Telmisartan (TELM) platinum(IV) complexes targeting EMT and tumor i...The epithelial-to-mesenchymal transition (EMT) and immunosuppressive tumor microenvironment (TME) are key drivers of tumor metastasis. Here, a series of Telmisartan (TELM) platinum(IV) complexes targeting EMT and tumor immunity were developed. A lead candidate was screened out that exhibited potent antiproliferative and antimetastatic activities both in vitro and in vivo. It effectively induced DNA damage and upregulated the expression of γ-H2AX and p53, further triggering significant apoptosis via the mitochondria-mediated Bcl-2/Bax/caspase-3 pathway. Then, the Ang II/AT1R axis was suppressed by the TELM ligand. Subsequently, the JAK2/STAT3 and ERK1/2 pathways were downregulated, while the hypoxic microenvironment was also reversed by inhibiting HIF-1α/VEGFA and MMPs signaling. As a result, the EMT process was abrogated by modulating -cadherin, -cadherin, and Vimentin. Additionally, the immunosuppressive TME was reprogrammed by blocking the immune checkpoint PD-L1 and inducing immunogenic cell death, and the infiltration density of CD3 and CD8 T cells was increased in tumor tissues.
Cannabinoid receptors are both therapeutically attractive and are interesting model systems for structure-based methods. Here we investigated topical questions in library docking using the CB2 receptor. While a CB1R dock...Cannabinoid receptors are both therapeutically attractive and are interesting model systems for structure-based methods. Here we investigated topical questions in library docking using the CB2 receptor. While a CB1R docking campaign found potent but nonselective ligands, here subtype selective ligands were found by targeting polar residues. Hit rates and hit affinities improved with library size, but docking against active and inactive receptor states did not reliably bias toward agonists or antagonists. Cryo-EM structures of two of the new agonists superposed well on the docking predictions. Structure-based optimization led to 10- to 140-fold improvements within three series, consistent with well-behaved ligands. Hit rates with an explicit 2.6 billion molecule library resembled those of an implied 11 billion molecule library from a building-block method, supporting the latter's ability to explore this space, though higher affinities were discovered from the explicit set. Implications for future studies are considered.
Amides and trifluoromethyl groups are among the most widely used structural motifs in materials science, medicinal chemistry, and agrochemistry. In contrast, their direct combination as -trifluoromethyl amides and the cl...Amides and trifluoromethyl groups are among the most widely used structural motifs in materials science, medicinal chemistry, and agrochemistry. In contrast, their direct combination as -trifluoromethyl amides and the closely related -trifluoromethyl carbamates and ureas has remained largely unexplored. This disconnect has primarily stemmed from the lack of synthetic methods and their unknown stabilities and physicochemical properties. Enabled by recently developed methodologies to synthesize -trifluoromethyl carbonyl compounds, we systematically evaluated their aqueous stability and drug-relevant properties to assess their usefulness for compound optimization. All investigated -trifluoromethyl derivatives display high aqueous stability at pH 7.4, including in human plasma, except for one -trifluoromethyl carbamate series. -Trifluoromethyl carbonyl motifs have a lipophilicity and Caco-2 permeability similar to their -isopropyl analogues, while, in several cases, offering improved pharmacokinetic profiles. These findings establish -trifluoromethyl carbonyl motifs as highly attractive functionalities, providing medicinal chemists with a framework for their incorporation into future drug-discovery programs.
Herein, we have designed, synthesized, and characterized four Os(II) photocatalysts, , [Os(phtpy)](PF) (), [Os(CF-phtpy)](PF) (), [Os(OH-phtpy)](PF) (), and [Os(quinoline-tpy)](PF) (). exhibited high absorption in the r...Herein, we have designed, synthesized, and characterized four Os(II) photocatalysts, , [Os(phtpy)](PF) (), [Os(CF-phtpy)](PF) (), [Os(OH-phtpy)](PF) (), and [Os(quinoline-tpy)](PF) (). exhibited high absorption in the red region, making them suitable candidates for red-light-triggered catalytic anticancer applications. SC-XRD analysis of and confirmed the distorted octahedral geometry of the OsN core. Theoretical studies provided insight into the electronic structure and excited-state properties of . Under red light (633 nm, 27 mW cm), exhibited selective NADH oxidation with TOF up to 13.70 h and efficient ROS generation (Φ up to 0.25). As a consequence, exhibited pronounced red-light-triggered anticancer activity against MDA-MB-231, MCF-7, and HeLa cells. Moreover, studies using an orthotopic mouse model revealed that significantly reduced tumor volume in a dose-dependent manner upon 650 nm laser (90 J cm) exposure by upregulating and downregulating , while it had good biosafety in the dark.
Novel selenium-containing small molecule PD-L1 inhibitors were designed and synthesized for the first time to explore their potential as antitumor agents. By computer-aided structural optimization, HTRF and SPR technique...Novel selenium-containing small molecule PD-L1 inhibitors were designed and synthesized for the first time to explore their potential as antitumor agents. By computer-aided structural optimization, HTRF and SPR techniques, compound was identified as the most potent blocker of the PD-1/PD-L1 interaction, exhibiting an IC value of 5.2 ± 0.5 nM, a value of 9.06 ± 1.25 nM, respectively. Study on the /hPD-L1 cocrystal structure (2.9 Å) revealed a unique selenomethyl-involved binding mode, which may interpret its superior inhibitory activity compared to other analogs. Cell-based assays showed that can mediate the internalization of PD-L1 and strongly block hPD-1 and hPD-L1 interaction, demonstrating its effectiveness in biological events. Notably, in the Hu-PD-L1 MC38 mouse model, significantly inhibited tumor growth, with a tumor growth inhibition (TGI) rate of 77.79% (60 mg/kg, administrated intragastrically) with no observable toxicity. These data indicate that is a promising and safe novel antitumor agent worthy of further development.
Selective degradation of mitochondrial proteins remains a significant challenge due to the unique compartmentalization and proteostasis mechanisms of this organelle. Here, we report , a mitochondria-targeted small-molecu...Selective degradation of mitochondrial proteins remains a significant challenge due to the unique compartmentalization and proteostasis mechanisms of this organelle. Here, we report , a mitochondria-targeted small-molecule degrader that selectively eliminates pyruvate dehydrogenase kinases (PDKs) by recruiting the mitochondrial protease HsClpP, achieving nanomolar degradation potency (DC0 ≈ 10 nM). Mechanistically, induces efficient pan-PDK degradation, thereby rewiring mitochondrial metabolism toward enhanced oxidative phosphorylation. This metabolic shift promotes the accumulation of reactive oxygen species (ROS), leading to opening of the mitochondrial permeability transition pore (mPTP) and activation of the intrinsic mitochondrial apoptosis. Notably, also elicits hallmark features of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release, thereby stimulating antitumor immune responses. Consistent with these findings, markedly suppresses both primary and distal tumor growth, with selective PDK degradation in tumor tissues and no observable systemic toxicity. Collectively, these results establish mitochondria-targeted degradation of metabolic enzymes as a promising therapeutic strategy for cancer.
Glutathione--transferase pi (GSTP1), overexpressed in cancer cells, is known to inactivate many electrophilic anticancer drugs by glutathionylation. While NBDHEX is a potent and selective inhibitor of GSTP1 with good ant...Glutathione--transferase pi (GSTP1), overexpressed in cancer cells, is known to inactivate many electrophilic anticancer drugs by glutathionylation. While NBDHEX is a potent and selective inhibitor of GSTP1 with good anticancer activity, it suffers from poor aqueous solubility and bioavailability. Herein, we report the reactive oxygen species (ROS)-responsive fluorogenic prodrug of NBDHEX, by coupling it to a dual positively charged NIR fluorophore () and a ROS-responsive unit. ROS-mediated activation of in aqueous medium resulted in rapid uncaging of NBDHEX, with turn-on NIR fluorescence and potent GSTP1 inhibition. Moreover, exhibited potent anticancer activity against triple-negative breast cancer (MDA-MB-231) cells compared with nonmalignant cells, with the modulation of key cancer marker genes. Endogenous ROS-mediated activation of led to the turn-on red fluorescence, which was further validated in developing zebrafish embryos, confirming the concomitant release of without any noticeable abnormalities or acute toxicities, supporting the translational potential of the prodrug.
Protein-protein interactions dominated by large, flat interfaces are widely considered challenging drug targets. The programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) immune checkpoint exemplifies th...Protein-protein interactions dominated by large, flat interfaces are widely considered challenging drug targets. The programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) immune checkpoint exemplifies this problem, as the interaction is mediated by an extended β-sheet surface lacking deep pockets. Despite this, PD-L1 has been successfully inhibited by chemically distinct modalities, including antibodies, macrocyclic peptides, and small molecules. Here, we present a comparative, structure-driven analysis of PD-L1 complexes deposited in the Protein Data Bank and demonstrate a striking convergence: all effective inhibitors engage the same CC'FG β-sheet face of PD-L1. Antibodies directly occlude this surface, macrocyclic peptides such as pAC65 reproduce antibody-like surface coverage in a compact and preorganized scaffold, and biphenyl small molecules neutralize the same epitope indirectly by inducing PD-L1 homodimerization. This unified structural framework reveals modality-agnostic design principles for targeting flat immune checkpoint PPIs. This Perspective provides a unified structural framework for understanding PD-L1 inhibition across clinically tested antibodies, macrocyclic peptides, and small molecules. Both visualizing and quantitatively comparing interface overlap, hotspot conservation, and buried surface area, the work demonstrates that distinct inhibitory modalities converge on the same functional CC'FG hotspot region while employing fundamentally different neutralization mechanisms. These findings establish structure-guided principles for the rational design of next-generation PD-L1 modulators across diverse therapeutic modalities.
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a cytosolic enzyme expressed primarily in hematopoietic cells that negatively regulates T cell signaling and antitumor immune response. Genetic and pharmacolog...Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a cytosolic enzyme expressed primarily in hematopoietic cells that negatively regulates T cell signaling and antitumor immune response. Genetic and pharmacological studies have demonstrated that PTPN22 is a systemic immunotherapy target that can enhance T cell activation and function when abrogated, resulting in reduced tumor burden. Building on our previously reported PTPN22 inhibitor, , we present the design, synthesis, and biological evaluation of a novel series of quinolone-3-carboxylic acid-based inhibitors. In addition to gaining new insights into the structure-activity relationship of this scaffold, compound displays improved potency, selectivity, and cellular efficacy compared to . Notably, exhibits a more favorable pharmacokinetic profile and drug properties, including oral bioavailability. Finally, is superior to in reducing MC38 tumor growth by promoting robust antitumor immunity, thus offering a promising lead molecule for the development of novel anticancer agents targeting PTPN22.
Peptidyl-prolyl - isomerase Pin1 is a promising anticancer target that is overexpressed in numerous cancers and associated with poor prognosis. Herein, two series of covalent Pin1 inhibitors featuring an ()- or a ()-4-ox...Peptidyl-prolyl - isomerase Pin1 is a promising anticancer target that is overexpressed in numerous cancers and associated with poor prognosis. Herein, two series of covalent Pin1 inhibitors featuring an ()- or a ()-4-oxobut-2-enoate moiety as the electrophilic warhead were discovered, and their binding features were revealed by six cocrystal structures. The binding kinetic investigations revealed that both ()- and ()-4-oxobut-2-enoate warheads exhibited an appropriate electrophilic activity ( = 0.006-3.60 min), conferring them as favorable covalent warheads for developing potent Pin1 inhibitors. The SAR investigations resulted in four ()-isomers (, : enzymatic IC = 0.02-0.08 μM) with excellent enzymatic activity, while the ()-isomer (enzymatic IC = 1.54 μM) was found to potently suppress the proliferation of MDA-MB-468 cancer cells by downregulating the Pin1 substrates c-Myc and Cyclin D1. Altogether, 4-oxobut-2-enoate derivatives were disclosed as new templates for further developing potent covalent Pin1 inhibitors.
Ezzat MAF, Seif EM, Nassar H
… +11 more, Bonardi A, Ferraroni M, Attia AA, Khater YTT, Rasheed RA, Abd El-Ghafar OAM, Allam HA, Angeli A, Schmidt M, Supuran CT, Ibrahim HS
In this study, new sulfonamide derivatives and were designed, synthesized, and biologically evaluated for their anti-inflammatory activity. In vitro COX inhibitory assays were performed, and among the synthesized compo...In this study, new sulfonamide derivatives and were designed, synthesized, and biologically evaluated for their anti-inflammatory activity. In vitro COX inhibitory assays were performed, and among the synthesized compounds, and emerged as the most promising leads, combining COX-2 inhibition with remarkable selectivity (COX-2 IC = 0.13 and 0.05 μM, SI = 9.25 and 12.02, respectively) and CA II inhibition ( = 39.1 nM and 62.6 nM, respectively) with a high selectivity index over CA I (SI = 933.8 and 704.2, respectively). In vivo evaluations confirmed that compounds and (50 mg/kg) possess promising analgesic and anti-inflammatory effects, with rapid onset, sustained duration of action, and a reduced ulcerogenic liability, indicating an improved gastrointestinal safety profile. Additionally, showed significant and sustained IOP-lowering effects in antiglaucoma animal models. Computational studies and X-ray crystallography were performed as a proof of concept.
Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, characterized by excessive inflammation, coagulation imbalance, and endothelial dysfunction, often progressing to multiple organ...Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, characterized by excessive inflammation, coagulation imbalance, and endothelial dysfunction, often progressing to multiple organ dysfunction and death. Small-molecule agents have emerged as promising therapeutic candidates by targeting key pathogenic pathways, including microbial clearance, immunomodulation, restoration of coagulation homeostasis, endothelial protection, and metabolic support. We summarize recent progress in small-molecule therapies for sepsis, focusing on their molecular targets, structural characteristics, pharmacological effects, and mechanisms of action. Although many candidates have shown encouraging results in preclinical and early clinical studies, their safety and efficacy remain to be confirmed in large-scale trials. To date, no small-molecule drug specifically targeting the core pathophysiology of sepsis has been approved, and most compounds are still under development.
() is the leading cause of hospital-acquired life-threatening diarrhea. toxins TcdA and TcdB contain a glucosyltransferase domain (GTD) that glucosylates and inactivates host GTPases, disrupting the actin cytoskeleton a...() is the leading cause of hospital-acquired life-threatening diarrhea. toxins TcdA and TcdB contain a glucosyltransferase domain (GTD) that glucosylates and inactivates host GTPases, disrupting the actin cytoskeleton and compromising epithelial integrity. TcdB, the most potent virulence factor, drives disease progression and is a high-priority target fortreatment and prevention. The iminosugar isofagomine has been shown to inhibit the GTD activity of TcdB by an uncompetitive inhibition mechanism, but requires the uridine 5'-diphosphate (UDP) reaction product. Compound classes synthesized here, ranging from isofagomine analogues to acyclic mimics, probe which modifications can tap into UDP-binding energy to enhance inhibition. Structure-activity relationship studies of isofagomine derivatives demonstrate remarkable specificity for isofagomine and limited advantage in accessing the UDP-binding site. Fluorescence and absorbance assays allowed facile inhibition assessment of TcdB's UDP-glucose hydrolysis. The molecules reported here guide scaffolds for future catalytic site inhibitors.
To enable real-time imaging of boron delivery with cellular resolution, a series of fluorescent [B] compounds was developed via a one-step synthesis using cost-effective, scalable reagents. The tumor-targeting agent, , a...To enable real-time imaging of boron delivery with cellular resolution, a series of fluorescent [B] compounds was developed via a one-step synthesis using cost-effective, scalable reagents. The tumor-targeting agent, , allowed noninvasive monitoring to identify the optimal time point for boron neutron capture therapy (BNCT) based on peak tumor accumulation. Fluorescence imaging analysis revealed a heterogeneous intratumoral distribution of , confirming that macroscopic accumulation does not equate to microscopic uniformity and emphasizing the need for improved tumor penetration in next-generation boron carriers. Furthermore, demonstrated efficacy for fluorescence-guided surgery in prostate cancer, suggesting a potential synergistic strategy to combine precise resection with BNCT for improved therapeutic outcomes.