Vascular endothelial growth factor receptors (VEGFRs) represent pivotal targets in cancer therapy, and developing highly potent VEGFR2 inhibitors remains a prominent research focus. Herein, leveraging structure-based rational design strategies involving scaffold hopping and substitution site variation, multiple series of novel naphthalene-scaffolded VEGFR2 inhibitors were synthesized and systematically evaluated. A representative compound, E20, was demonstrated as a multitargeted tyrosine kinase inhibitor exhibiting subnanomolar IC50 value against VEGFR2 and broad-spectrum antiproliferative potency in vitro, which significantly outperformed lenvatinib. Mechanistically, E20 potently suppressed VEGFR2 and downstream AKT/ERK phosphorylation, while inhibiting HUVEC proliferation, tube formation, and migration. Notably, oral administration of E20 remarkably inhibited hepatocellular, lung, renal, and thyroid tumor growth in vivo with tumor growth inhibition rates exceeding 90%, far superior to those of lenvatinib. Moreover, E20 showed favorable pharmacokinetics, improved tolerability, and a wider therapeutic window than lenvatinib. Collectively, these results validate E20 as a promising preclinical candidate for treating diverse solid tumors.

Immunosuppressive Tregs, regulated by IKZF2, facilitate tumor immune evasion and resistance to immune checkpoint therapies. Targeted IKZF2 degradation represents a promising strategy for the development of innovative cancer immunotherapeutics. Herein, we designed and synthesized a novel series of phthalazinone-based glutarimide derivatives, identifying compound 25 as a potent, highly selective, and rapid-acting IKZF2 molecular glue degrader. Compound 25 induced robust IKZF2 degradation (DC50 = 1.78 nM and Dmax = 93.2%) via a Cullin-CRBN-dependent pathway, while sparing other CRBN neosubstrates and outperforming the benchmark degrader DKY709. Mechanistically, 25-induced IKZF2 deletion enhanced the proinflammatory IL-2 production and attenuated the immunosuppressive function of Tregs. Oral administration of 25 triggered rapid, profound, and sustained IKZF2 degradation in mice spleen and thymus. As monotherapy, 25 significantly suppressed B16F tumor growth, and 25 combined with anti-PD-1 antibody therapy exhibited marked synergistic effects. Together, our findings demonstrate 25 as a promising IKZF2 degrader for advancing cancer immunotherapy.

PROTACs are revolutionary therapeutics that eliminate pathogenic proteins via catalytic event-driven degradation. Conventional development suffers from unpredictable ternary complexes, empirical linker modification and blind ligand screening, yielding clinical success below 10% and requiring 3-4 years to obtain preclinical candidates. Generative artificial intelligence (AI) offers a promising avenue for data-driven rational design. This perspective explores how multimodal deep learning enhances ternary complex prediction accuracy and boosts molecular design hit rates from 5-8% to over 35%. Closed-loop research and development (R&D) ecosystems supported by databases accelerate PROTAC development. The landmark case of Insilico Medicine’s PKMYT1-PROTAC, developed via its AI platform Chemistry 42, achieves a DC50 of 0.5 nM and exhibits a dual degradation-inhibition mechanism, and has advanced to the preclinical candidate (PCC) validation stage within approximately 12 months. We further discuss how to integrate AI design with clinical translation. Future efforts focus on advanced computational strategies, establishing standardized evaluation metrics and expanding the E3 ligase toolbox. This AI-powered strategy will expedite PROTAC research and expand the application of targeted protein degradation therapy.

The von Hippel-Lindau tumor suppressor (VHL) has been extensively used to develop degraders targeting numerous proteins of interest. However, studies on the rational design of VHL-proteolysis-targeting chimeras (PROTACs) remain scarce. This study aimed to develop strategies to investigate VHL-recruiting PROTACs connecting with varying attachment sites on VHL ligands, which could be utilized for KRAS(G12C) degraders development and expanded to additional targets. We developed a molecular dynamics (MD)-based strategy to explore the stability of ternary complexes induced by KRAS(G12C) PROTACs with four distinct attachment sites of VH032. We found a potent degrader namely YN14-H, linked to hydroxyl group on VH032 benzene ring, exhibited the most superior ability of inducing ternary complexes, reflected by the lowest dissociation constant (K-d) for ternary complex induction and the highest AlphaScreen (AS)-based interaction. YN14-H inhibited cell growth with low nanomolar half maximal inhibitory concentration (IC50) and half maximal degradation concentration (DC50) values as well as >98 % of maximum degradation (D-max) in NCI-H358 and MIA PaCa-2 cells harboring KRAS(G12C)-mutation. Mechanistically, YN14-H significantly induced apoptosis and inhibited the migratory capacity. Notably, YN14-H demonstrated favorable pharmacokinetic properties and excellent antitumor activity in vivo. Furthermore, bromodomain-containing protein 7 (BRD7) and Bruton tyrosine kinase (BTK) degraders attached to distinct sites on VH032 further verified the rationality and universality of our MD-based strategies. Our findings demonstrated that YN14-H could serve as a promising candidate for the treatment of tumors with KRAS(G12C)-mutation and present a strategy for the rational design of VHL-recruiting PROTACs that target additional proteins at distinct attachment sites. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Acute lung injury (ALI) pathogenesis is intricately linked to microvascular permeability. Soluble guanylate cyclase (sGC) is prominently expressed in the vascular system, playing a central role in vascular function. In contrast, its expression and function diminish notably during the progression of ALI, indicating sGC's potential significance as a pivotal modulator in the pathological processes of ALI. Nonetheless, the precise localization of sGC within lung tissue and its distinct mechanism in maintaining vascular homeostasis remain unclear. Furthermore, there is a necessity for a pharmacological agent capable of consistently activating sGC for the treatment of ALI. A novel sGC stimulator, sGC003, was engineered through structural modification of Riociguat. In a mouse model of ALI, sGC003 exhibited superior sGC activation and more potent anti-inflammatory effects relative to Riociguat. It also exhibited superior efficacy in improving respiratory function and reducing pulmonary edema. Through single-cell RNA sequencing and immunofluorescence co-localization analysis, we confirmed predominant expression of soluble guanylate cyclase in pericytes. The sGC stimulators were found to modulate the LPS-induced pericyte transcriptome reprogramming via the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway. Differential gene expression analysis categorized pericytes into nine distinct subgroups, which were sequentially activated during vascular development, inflammation, and myofibrosis. Pseudotime analysis revealed that sGC003 more effectively suppressed the myofibroblast differentiation of pericytes compared to Riociguat. In conclusion, sGC003 mitigates ALI-induced pulmonary inflammation by modulating pericyte differentiation, particularly in preserving microvascular integrity outstanding performance. Its exceptional efficacy suggests that it could potentially serve as a safer and more efficient option as a novel sGC stimulant in the future.

Immunomodulatory drugs (IMiDs) are widely utilized therapies in multiple hematological cancers; however, their clinical application is frequently constrained by drug resistance. Here, though screening of diverse cereblon (CRBN) binders, comprehensive structure-activity relationships (SAR) analyses and systematic degradation profiling, MGD-22, a potent IKZF1/2/3 degrader featuring a phthalazinone scaffold, demonstrated nanomolar-range IC50 potencies across diverse multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL) cancer cells and overcame acquired resistance to pomalidomide. MGD-22 selectively induced robust degradation of IKZF1/2/3 in a Cullin-CRBN pathway-dependent manner, with nanomolar DC50 potency. Furthermore, orally administered MGD-22 demonstrated significant tumor growth inhibition with admirable pharmacokinetic properties and displayed s marked synergistic effects with Bruton's tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitor, respectively, in DLBCL cancer cells. Collectively, these findings establish a rationale for triple-targeted degradation of IKZF1/2/3 and position MGD-22 as a promising therapeutic candidate with broader applicability in hematological cancer treatment.

As a key driver of tumorigenesis and cancer development, the KRASG12D mutation is ubiquitous existed in KRAS-associated malignancies, highlighting the urgent clinical need for effective KRASG12D targeting drugs. In this study, through rational design and multiple cell type-based antiproliferative evaluation, we identified a novel KRASG12D inhibitor, Y-I-1, which demonstrated remarkable anti-cancer activity. Subsequent computational analyses including molecular dynamics (MD) simulations, binding free energy calculations, umbrella sampling, and protein-ligand docking revealed its excellent binding characteristics, rationalizing the observed potency. Building upon the structure of Y-I-1, we constructed proteolysis-targeting chimera (PROTAC) by conjugating it with different linker moieties and VH032. Among them, degrader Y-D-2 potently and selectively exhibited nanomolar inhibitory IC50, degradation DC50 values, and more than 95 % maximum degradation (Dmax) in KRASG12D-mutant cancer cells via ubiquitin proteasome-involving pathway, accompanied by nanomolar IC50 efficiency for phosphorylated ERK (pERK) inhibition. Mechanistically, Y-D-2 significantly induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, Y-D-2 led to significant tumor growth inhibition in the GP2D xenograft model with well-tolerated dose-schedules with favorable PK properties. This study not only provides an important theoretical basis for the optimal design of KRASG12D degraders, but also highlights its potential for the treatment of KRASG12D-driven cancers.

The cGAS-STING pathway is pivotal for innate immunity and antitumor responses. However, the challenge of selectively targeting the diseased tissue without harming the healthy tissue has impeded the development of STING agonists. In this article, we tackle this issue by developing novel STING synergists that target the STING C-terminal domain pocket. Our findings indicate that agonist 12B can boost the cGAMP-STING pathway synergistically. Through reverse optimization of 12B, we synthesized three series of compounds, with compounds 55, 66, and 67 emerging as selective STING synergists that amplify cGAMP-induced pathway activation without inherent agonist properties. Compound 67 emerged as the most potent (EC50 = 20.53 μM), displaying a broad binding affinity across STING-CTD alleles and potent antitumor efficacy in vivo. Notably, it exhibited excellent safety profiles in both in vitro and in vivo models, along with favorable pharmacokinetics. These findings highlight the therapeutic potential of novel STING synergists for cancer immunotherapy.

In Gram-negative bacteria, lipopolysaccharides (LPSs, also known as endotoxin) can induce extensive immune responses that will enable victims to produce severe septic shock syndrome. Because of the high mortality of sepsis in the face of standard treatment, advance detoxification schemes are urgently needed in clinics. Herein, we described a supramolecular detoxification approach via direct host–guest complexation by a giant macrocycle. Cationic pentaphen[3]arene (CPP3) bearing multiple quaternary ammonium groups was screened as a candidate antidote. CPP3 exhibited robust binding affinity toward LPS with an association constant of (4.79 ± 0.29) × 108 M−1. Co-dosing with an equivalent amount of CPP3 has been demonstrated to decrease LPS-induced cytotoxicity on a cellular level through inhibiting ROS generation and proinflammatory cytokine expression. In vivo experiments have further proved that post-treatment by CPP3 could significantly improve the survival rate of LPS-poisoned mice from 0 to 100% over a period of 3 days, and inflammatory abnormalities and tissue damage were also alleviated.

Objectives:Immunomodulatory drugs (IMiDs), functioning as molecular glue degraders, have been approved for treating various hematological malignancies; however, the inevitable acquired drug resistance resulting from their skeletal similarity and hematological toxicities poses significant obstacles to their clinical treatment. The study aimed to develop degraders with potent efficiency and low toxicity. Methods:Phenotypic profiling, elaborate structure-activity relationships (SAR), rational drug design and degradation profiles investigations, quantitative proteomics analysis and cell-based functional studies, and pharmacokinetic studies were conducted to develop more potent degraders. Results:This study developed novel CRBN-binding moieties through methylene deletion in lenalidomide's isoindole core. Lead compounds MGD-A7 and MGD-C9 demonstrated superior antiproliferative efficacy vs. IMiDs, with submicromolar potency. MGD-A7 and MGD-C9 significantly and selectively induced the degradation of Ikaros Family Zinc Finger Proteins 1 and 3 (IKZF1/3) with nanomolar potency via a CRBN-dependent pathway. Mechanistically, MGD-A7 and MGD-C9 dramatically induced cell apoptosis and G1 cell cycle arrest and MGD-C9 exhibited favorable pharmacokinetic properties in vivo. Furthermore, MGD-C9 exhibited significant synergistic effects with standard-of-care agents in various hematological malignancy cells. Conclusions:These results indicate that MGD-C9 could act as a highly effective CRBN ligand and is expected to become a candidate drug for the treatment of hematological malignancies.

The cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target in multiple cancers. Despite various c-Met inhibitors having been developed, the acquired drug resistance hampers their clinical application. In this study, through elaborately rational optimization, c-Met degraders, namely, D19, D26, and G4, were developed to exhibit single-digit nanomolar cell growth inhibition IC50 values, picomolar c-Met degradation DC50 values, and >99% of maximum degradation in cancer cells with MET alterations via a Cullin-CRBN-dependent pathway. Moreover, D19 and G4 showed favorable pharmacokinetic properties and their oral administration induced complete EBC-1 xenograft tumor inhibition. Notably, D19 and G4 achieved nanomolar inhibitory activity and degradation efficacy against tepotinib-resistant cancer cells harboring c-MetD1228N and c-MetY1230H mutations. Furthermore, the synergetic effects of D19 with epidermal growth factor receptor/HER2, vascular endothelial growth factor receptor, and BRAF inhibitors were shown in inhibiting various types of tumor cells. Overall, this study demonstrates that D19 and G4 serve as promising candidates for the treatment of MET-driven cancers.

Despite remarkable achievements in antibody‒drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.

Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 +/- 0.61) x 10(7) M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.

RN -9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN -9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5 -fold increase in inhibitory potency against TRPV4 (IC 50 = 0.71 +/- 0.21 mu M and 0.46 +/- 0.08 mu M, respectively) in vitro , in comparison to RN -9893 (IC 50 = 2.07 +/- 0.90 mu M). Both compounds also significantly outperformed RN -9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 mu M, against RN-9893 ' s 49.4 %). For the first time, these RN -9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Previously we reported two salicylaldoxime conjugates (L7R3 and L7R5) showing equal or even higher reactivating efficiency for both organophosphorus nerve agent and pesticide inhibited acetylcholinesterase in comparison to obidoxime and HI-6. In this study, L7R3 and L7R5 were selected as lead compounds and refined by employing a fragment-based drug design strategy, and a total of 32 novel salicylaldoxime conjugates were constructed and screened for DFP and paraoxon inhibited acetylcholinesterase. The findings demonstrate that the conjugate L73R3, which contains a 4-nitrophenyl group, exhibited a higher reactivation efficacy against paraoxon-inhibited acetylcholinesterase compared to obidoxime and HI-6. It was confirmed that the combination of a 4-pyridinyl or 4-nitrophenyl peripheral site ligand, a piperazine linker and a methyl or chloro-substituted salicylaldoxime could construct efficient nonquaternary oxime reactivators. The results hold promise for developing a new generation of highly effective antidotes for organophosphate poisoning.

The α2A adrenergic receptor (α2A-AR) serves as a critical molecular target for sedatives and analgesics. However, α2A-AR ligands with an imidazole ring also interact with an imidazoline receptor as well as other proteins and lead to undesirable effects, motivating us to develop more novel scaffold α2A-AR ligands. For this purpose, we employed an ensemble-based ligand discovery strategy, integrating long-term molecular dynamics (MD) simulations and virtual screening, to identify new potential α2A-AR agonists with novel scaffold. Our results showed that compounds SY-15 and SY-17 exhibited significant biological effects in the preliminary evaluation of protein kinase A (PKA) redistribution assays. They also reduced levels of intracellular cyclic adenosine monophosphate (cAMP) in a dose-dependent manner. Upon treatment of the cells with 100 μM concentrations of SY-15 and SY-17, there was a respective decrease in the intracellular cAMP levels by 63.43% and 53.83%. Subsequent computational analysis was conducted to elucidate the binding interactions of SY-15 and SY-17 with the α2A-AR. The binding free energies of SY-15 and SY-17 calculated by MD simulations were −45.93 and −71.97 kcal/mol. MD simulations also revealed that both compounds act as bitopic agonists, occupying the orthosteric site and a novel exosite of the receptor simultaneously. Our findings of integrative computational and experimental approaches could offer the potential to enhance ligand affinity and selectivity through dual-site occupancy and provide a novel direction for the rational design of sedatives and analgesics.

INTRODUCTION:Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials.AREAS COVERED:This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs.EXPERT OPINION:By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

Abstract Iron ion is one of the most physiologically important elements in metabolic processes, indispensable for all living systems. Since its excess can lead to severe diseases, new approaches for its monitoring in water samples are urgently needed to meet requirements. Here, we firstly report a novel and universal route for the synthesis of a series of pillar[n]arene derivates containing one benzoquinone unit by photocatalysis. With this in hand, an anthracene – appended water – soluble pillar[5]arene (H) with excellent fluorescence sensing potency was prepared. H enabled the ultrasensitive detection of iron ions in aqueous solution with limits of detection of 10−8 M. Over a wide range of metal ions, H exhibited specific selectivity toward Fe3+. More importantly, H could still properly operate in a simulated sewage sample, coexisting with multiple interference ions.

GSK-Bz, a TPRV4 antagonist discovered by GSK, displayed potent in vitro TRPV4 inhibition activity, and demonstrated ability to inhibit TRPV4-mediated pulmonary edema in an in vivo rat model. In this study, a series of GSK-Bz derivatives were designed and synthesized based on our previous findings. Compound 2b with cyanocyclobutyl moiety (IC50 = 22.65 nM) was found to be 5.3-fold more potent than GSK-Bz (IC50 = 121.6 nM) in the calcium imaging experiment. Patch-clamp experiments confirmed that compound 2b (IR = 77.1%) also gave significantly improved potency on TRPV4 currents measured at -60 mV. Furthermore, 2b effectively suppressed the permeability response to LPS in HUVEC with negligible cytotoxicity (CC50 > 100 μM). The in vivo protective effects of compounds 2b on acute lung injury were finally assessed in an LPS-induced ALI mice model. Notably, 2b gave better results than HC-067047 against all of the tested indexes (lung W/D ratios, the concentrations of BALF protein and pathological scores), indicating that 2b is a novel and highly potent TRPV4 antagonist which is worth for further development. Currently, evaluation for the drug-like properties of 2b is underway.