Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

Metabolome evidence of CKDu risks after chronic exposure to simulated Sri Lanka drinking water in zebrafish.

It is still a serious public health issue that chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka poses challenges in identification, prevention, and treatment. What environmental factors in drinking water cause kidney damage remains unclear. This study aimed to investigate the risks of various environmental factors that may induce CKDu, including water hardness, fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM). The research focused on comprehensive metabolome analysis, and correlation with transcriptomic and gut microbiota changes. Results revealed that chronic exposure led to kidney damage and pancreatic toxicity in adult zebrafish. Metabolomics profiling showed significant alterations in biochemical processes, with enriched metabolic pathways of oxidative phosphorylation, folate biosynthesis, arachidonic acid metabolism, FoxO signaling pathway, lysosome, pyruvate metabolism, and purine metabolism. The network analysis revealed significant changes in metabolites associated with renal function and diseases, including 20-Hydroxy-LTE4, PS(18:0/22:2(13Z,16Z)), Neuromedin N, 20-Oxo-Leukotriene E4, and phenol sulfate, which are involved in the fatty acyls and glycerophospholipids class. These metabolites were closely associated with the disrupted gut bacteria of g_ZOR0006, g_Pseudomonas, g_Tsukamurella, g_Cetobacterium, g_Flavobacterium, which belonged to dominant phyla of Firmicutes and Proteobacteria, etc., and differentially expressed genes (DEGs) such as egln3, ca2, jun, slc2a1b, and gls2b in zebrafish. Exploratory omics analyses revealed the shared significantly changed pathways in transcriptome and metabolome like calcium signaling and necroptosis, suggesting potential biomarkers for assessing kidney disease.

Bisphenol A impairs macrophages through inhibiting autophagy via AMPK/mTOR signaling pathway and inducing apoptosis.

Bisphenol A (BPA) is a widespread endocrine disruptor that induces the impairment of immune cells, but the mechanism remains unknown. Macrophages are one of the most important immune cells in innate and adaptive immunity. In this study, we aimed to probe the effects of BPA on the damage of RAW264.7 cells and its mechanisms of action, especially focusing on the relationship between autophagy and apoptosis. Cells were pretreated with 10 mg/L LPS, or added autophagy activator RAPA, autophagy inhibitor 3-MA or Bcl-2 inhibitor ABT-737, then treated with BPA (0, 10, 100 and 200 µmol/L) for 12 h. Results have shown that BPA decreased the cell viability and disrupted secretory function by promoting pro-inflammatory cytokines TNF-α and IL-6 and reducing anti-inflammatory cytokines IL-10 TGF-ß, as well as phagocytic ability. Moreover, autophagy was inhibited by BPA through decreasing p-AMPK/AMPK and increasing p-mTOR/mTOR, and further down-regulating autophagy proteins ATG6, LC3II/I ratio, and up-regulating autophagy flux protein p62. Additionally, BPA significantly increased Bax/Bcl-2 ratio, Caspase-3 expression and apoptosis rate. We found that RAPA ameliorated the cell viability, Bax/Bcl-2 ratio, and macrophage function damage induced by BPA. Intriguingly, ABT-737 might promote ATG6 expression. In summary, our study demonstrated that the effects of BPA on macrophages seemed to be mediated by inhibiting AMPK/mTOR-dependent autophagy and inducing apoptosis via endogenous mitochondrial pathway. Both Bcl-2 and ATG6 were involved in the regulation of apoptosis and autophagy by BPA. These findings provide a broader perspective for understanding the interaction between autophagy and apoptosis in BPA-induced immune cell injury.

A Joint 2D-3D Complementary Network for Stereo Matching.

Stereo matching is an important research field of computer vision. Due to the dimension of cost aggregation, current neural network-based stereo methods are difficult to trade-off speed and accuracy. To this end, we integrate fast 2D stereo methods with accurate 3D networks to improve performance and reduce running time. We leverage a 2D encoder-decoder network to generate a rough disparity map and construct a disparity range to guide the 3D aggregation network, which can significantly improve the accuracy and reduce the computational cost. We use a stacked hourglass structure to refine the disparity from coarse to fine. We evaluated our method on three public datasets. According to the KITTI official website results, Our network can generate an accurate result in 80 ms on a modern GPU. Compared to other 2D stereo networks (AANet, DeepPruner, FADNet, etc.), our network has a big improvement in accuracy. Meanwhile, it is significantly faster than other 3D stereo networks (5× than PSMNet, 7.5× than CSN and 22.5× than GANet, etc.), demonstrating the effectiveness of our method.

DNMT3b-mediated methylation of ZSWIM3 enhances inflammation in alcohol-induced liver injury via regulating TRAF2-mediated NF-κB pathway.

The regulation of macrophages during inflammatory responses is a crucial process in alcoholic liver disease (ALD) and aberrant macrophage DNA methylation is associated with inflammation. Our preliminary screening results of macrophage methylation in the present study demonstrated the zinc finger SWI2/SNF2 and MuDR (SWIM)-domain containing 3 (ZSWIM3) were hypermethylated in the 5' untranslated region (5'-UTR) region. ZSWIM3, a novel zinc finger-chelate domain of SWIM, is predicted to function in DNA-binding and protein-binding interactions. Its expression was found to be consistently decreased in macrophages isolated from livers of ethyl alcohol (EtOH)-fed mice and in EtOH+lipopolysaccharide (LPS)-induced RAW264.7 cells. Over-expression of ZSWIM3 was found to attenuate chronic+binge ethanol feeding-induced liver injury and inhibit inflammatory responses in vivo. Enforced expression of ZSWIM3 in vitro was also found to have anti-inflammatory effects. Aberrant expression of ZSWIM3 in alcohol-induced liver injury (ALI) was found to be associated with hypermethylation. Analysis of CpG prediction indicated the presence of two methylated sites in the ZSWIM3 promoter region and methylation inhibitor and DNA methyltransferases (DNMTs)-siRNA transfection were found to restore down-regulated ZSWIM3. Chromatin immunoprecipitation (ChIP) assay and molecular docking affirmed the role of DNMT 3b (DNMT3b) as a principal regulator of ZSWIM3 expression. Mechanistically, ZSWIM3 might affect inflammation by binding with tumor necrosis factor receptor-associated factor 2 (TRAF2), which further mediates the activation of the nuclear transcription factor κB (NF-κB) pathway. The present study, therefore, provides detailed insights into the possible structure and function of ZSWIM3 and thus, contributes new substantial research in the elucidation of the pathogenesis of ALI.

Anti-Inflammatory Effect of Novel 7-Substituted Coumarin Derivatives through Inhibition of NF-κB Signaling Pathway.

A series of novel 7-substituted coumarin derivatives were synthesized and evaluated. Biological screening results obtained by the evaluation of the compounds' inhibition against LPS-induced IL-6 and TNF-α release in RAW 264.7 cells indicated that most compounds exhibited potent anti-inflammatory activity. Among them, N-(3-methoxybenzyl)-2-[(2-oxo-2H-chromen-7-yl)oxy]acetamide (2d) showed the best activity. The potential targets of title compound 2d were reversely screened with the molecular modeling software, Discovery Studio 2017 R2. Screening and molecule docking results showed that 2d could bind to the active site (NLS Polypeptide) of NF-κB p65, and this binding affinity was confirmed by surface plasmon resonance (SPR) analysis. Furthermore, Western blot assay showed that 2d remarkably blocked the NF-κB signaling pathway in vitro. Collectively, all these findings suggested that compound 2d might be a promising lead compound worthy of further pursuit.

Rutacecarpine Inhibits Angiogenesis by Targeting the VEGFR2 and VEGFR2-Mediated Akt/mTOR/p70s6k Signaling Pathway.

This study aimed to investigate the effect of Ru (Rut) on angiogenesis, and the underlying regulation mechanism of signal transduction. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, adhesion inhibition experiment, migration inhibition experiment, and chick embryo chorioallantoic membrane (CAM) assays were performed on models of angiogenesis. The potential targets of rutaecarpine (Ru) were reverse screened with Discovery Studio 2017. The interaction between the compound and target were detected by surface plasmon resonance (SPR), enzyme-activity experiment, and Western blot assay. The obtained results confirmed that Ru exhibited modest inhibitory activity against human umbilical vein endothelial cells (HUVECs) (IC50 =16.54 ± 2.4 µM) and remarkable inhibitive effect against the migration and adhesion of HUVECs, as well as significant anti-angiogenesis activities in the CAM assay. The possible targets of vascular endothelial growth factor receptor 2 (VEGFR2) were identified by computer-aided simulation. Results showed a good binding relationship between the ligand and target through molecular docking, and this relationship was confirmed by SPR analysis. Furthermore, enzyme-activity experiment and western blot assay showed that Ru remarkably inhibited the activity of VEGFR2 and blocked the VEGFR2-mediated Akt/ (mTOR)/p70s6k signaling pathway in vitro. Ru can be a potential drug candidate for cancer prevention and cancer therapy.

Investigation of Phenolic Resin-Modified Asphalt and Its Mixtures.

This study comprehensively examines the influence of phenol-formaldehyde resin (PF) on the performance of base asphalt and its mixtures for road applications, emphasizing its innovative use in enhancing pavement quality. Optimal PF content was determined through the evaluation of standard indicators and rotational viscosity. In-depth analyses of PF-modified asphalt's high- and low-temperature rheological properties and viscoelastic behavior were conducted using dynamic shear rheometers and bending beam rheometers. Aging resistance was assessed through short-term aging and performance grade (PG) grading. Moreover, Marshall and water stability tests were performed on PF-modified asphalt mixtures. Findings indicate that the uniform dispersion of PF particles effectively inhibits asphalt flow at high temperatures, impedes oxygen penetration, and delays the transition from elasticity to viscosity. These unique properties enhance the high-temperature stability, rutting resistance, and aging resistance of PF-modified asphalt. However, under extremely low temperatures, PF's brittleness may impact asphalt flexibility. Nonetheless, the structural advantages of PF-modified asphalt, such as improved mixture density and stability, contribute to enhanced high-temperature performance, water stability, adhesion, and freeze-thaw cycle stability. This research demonstrates the feasibility and effectiveness of using PF to enhance the overall performance of base asphalt and asphalt mixtures for road construction.

Generation, Maintenance, and Identification of Germ-Free Zebrafish Models from Larvae to Juvenile Stages.

Zebrafish serve as valuable models for research on growth, immunity, and gut microbiota due to their genomic similarities with mammals, transparent embryos developed in a relatively clean chorion environment, and extremely rapid development of larvae compared to rodent models. Germ-free (GF) zebrafish (Danio rerio) are crucial for evaluating pollutant toxicity and establishing human-like disease models related to microbial functions. In comparison to conventionally raised (CR) models (fish in common husbandry), GF zebrafish allow for more accurate manipulation of the host microbiota, aiding in determining the causal relationship between microorganisms and hosts. Consequently, they play a critical role in advancing our understanding of these relationships. However, GF zebrafish models are typically generated and researched during the early life stages (from embryos to larvae) due to limitations in immune function and nutrient absorption. This study optimizes the generation, maintenance, and identification of early GF zebrafish models without feeding and with long-term feeding using GF food (such as Artemia sp., brine shrimp). Throughout the process, daily sampling and culture were performed and identified through multiple detections, including plates and 16S rRNA sequencing. The aseptic rate, survival, and developmental indexes of GF zebrafish were recorded to ensure the quality and quantity of the generated models. Importantly, this study provides details on bacterial isolation and infection techniques for GF fish, enabling the efficient creation of GF fish models from larvae to juvenile stages with GF food support. By applying these procedures in biomedical research, scientists can better understand the relationships between intestinal bacterial functions and host health.

Control effect and field application of four predatory Orius species on Megalurothrips usitatus (Thysanoptera: Thripidae).

Megalurothrips usitatus (Bagrall) is one of the most important pests of cowpea, Vigna unguiculata (Linn.) Walp in South China. Four Orius species, including Orius minutus (L.), Orius nagaii (Yasunaga), Orius sauteri (Poppius), and Orius strigicollis (Poppius), have been commercially produced and widely used as natural enemies of pests in China. In this study, we evaluated the control efficiency of these Orius species on M. usitatus in tropical Hainan Province, China, by recording the survival rates, developmental times, and predation effects in laboratory and semi-field conditions. Laboratory experiments showed that all these 4 Orius species preyed on M. usitatus under the experimental temperatures (25, 30, and 35 °C), and O. strigicollis exhibited the highest survival rate and predation effect. Semi-field cage experiments showed that the control effect of 4 Orius species on M. usitatus was significantly higher than that under normal chemical control, with O. strigicollis having the highest effect. Greenhouse experiments in Hainan Province, China, confirmed that O. strigicollis had a significant control effect on M. usitatus. Our study indicated that O. strigicollis has a significant potential for the control of M. usitatus in cowpea fields in southern China.

Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody.

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy. Systematically structure-activity relationship (SAR) exploration led to the identification of F03 (HMC-B17). The representative compound, HMC-B17, showed the potent HPK1 inhibition with an IC50 value of 1.39 nM and favorable selectivity against TCR-related kinases. In addition, the HMC-B17 effectively enhanced the IL-2 secretion in Jurkat cells (EC50 = 11.56 nM). Strikingly, immune-reverse effects and improved immune response in vivo were observed after HMC-B17 treatment. Furthermore, HMC-B17 combined with anti-PD-L1 antibody demonstrated a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model. Collectively, our findings suggest that HMC-B17 could be a valuable lead compound to develop a safe and potent HPK1 inhibitor for further cancer immunotherapy.

Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells. Compound C3, featuring a 4-methylpiperidine ring linker, effectively degraded CDK2 with a DC50 value of 18.73 ± 10.78 nM, and stimulated 72.77 ± 3.51 % cell differentiation at 6.25 nM in HL-60 cells. Moreover, C3 exhibited potent anti-proliferative activity against various AML cell types. Degradation selectivity analysis indicated that C3 could be endowed with efficient degradation of CDK2/4/6/9 and FLT3, especially FLT3-ITD in MV4-11 cells. These findings propose that C3 combined targeting CDK2/4/6/9 and FLT3 with enhanced differentiation and proliferation inhibition, which holds promise as a potential treatment for AML.

Rational Identification of Novel Antibody-Drug Conjugate with High Bystander Killing Effect against Heterogeneous Tumors.

Bystander-killing payloads can significantly overcome the tumor heterogeneity issue and enhance the clinical potential of antibody-drug conjugates (ADC), but the rational design and identification of effective bystander warheads constrain the broader implementation of this strategy. Here, graph attention networks (GAT) are constructed for a rational bystander killing scoring model and ADC construction workflow for the first time. To generate efficient bystander-killing payloads, this model is utilized for score-directed exatecan derivatives design. Among them, Ed9, the most potent payload with satisfactory permeability and bioactivity, is further used to construct ADC. Through linker optimization and conjugation, novel ADCs are constructed that perform excellent anti-tumor efficacy and bystander-killing effect in vivo and in vitro. The optimal conjugate T-VEd9 exhibited therapeutic efficacy superior to DS-8201 against heterogeneous tumors. These results demonstrate that the effective scoring approach can pave the way for the discovery of novel ADC with promising bystander payloads to combat tumor heterogeneity.

Improved Environmental Stimulus and Biological Competition Tactics Interactive Artificial Ecological Optimization Algorithm for Clustering.

An interactive artificial ecological optimization algorithm (SIAEO) based on environmental stimulus and a competition mechanism was devised to find the solution to a complex calculation, which can often become bogged down in local optimum because of the sequential execution of consumption and decomposition stages in the artificial ecological optimization algorithm. Firstly, the environmental stimulus defined by population diversity makes the population interactively execute the consumption operator and decomposition operator to abate the inhomogeneity of the algorithm. Secondly, the three different types of predation modes in the consumption stage were regarded as three different tasks, and the task execution mode was determined by the maximum cumulative success rate of each individual task execution. Furthermore, the biological competition operator is recommended to modify the regeneration strategy so that the SIAEO algorithm can provide consideration to the exploitation in the exploration stage, break the equal probability execution mode of the AEO, and promote the competition among operators. Finally, the stochastic mean suppression alternation exploitation problem is introduced in the later exploitation process of the algorithm, which can tremendously heighten the SIAEO algorithm to run away the local optimum. A comparison between SIAEO and other improved algorithms is performed on the CEC2017 and CEC2019 test set.

C-scheme electron transfer mechanism: An efficient ternary heterojunction photocatalyst carbon quantum dots/Bi/BiOBr with full ohmic contact.

With a facile one-pot solvothermal method, an efficient ternary heterojunction photocatalyst carbon quantum dots (CQDs)/Bi/BiOBr is firstly prepared. Ethylene glycol (EG) is used as the solvent and carbon source for the first time. At 190 °C for 3 h, while BiOBr is synthesized, EG is employed to prepare CQDs through bottom-up method. CQDs are grafted by a large number of functional groups with reducibility, which reduce some neighboring BiO+ to metal Bi. By modifying the solvothermal temperature and time, CQDs and Bi are in-situ controllably deposited on the surface of BiOBr microspheres. Due to different Fermi levels and work functions, the interfaces of CQDs, BiOBr and Bi are connected through ohmic junctions with low contact impedance. The hot electrons from Bi with surface plasmon resonance (SPR) properties, and electrons in the CB of BiOBr flow to CQDs, forming a C-scheme electron transfer mechanism. O2- from CQDs and h+ in the VB of BiOBr respectively attack the sites with higher and lower electron density in methyl orange (MO) molecule, resulting in its photodegradation into small molecular products.

Overseas immigration of fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), invading Korea and Japan in 2019.

The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith), spread rapidly in Africa and Asia recently, causing huge economic losses in crop production. Fall armyworm caterpillars were first detected in South Korea and Japan in June 2019. Here, the migration timing and path for FAW into the countries were estimated by a trajectory simulation approach implementing the insect's flight behavior. The result showed that FAWs found in both South Korea and Japan were estimated to have come from eastern China by crossing the Yellow Sea or the East China Sea in 10-36 h in three series of migrations. In the first series, FAW moths that arrived on Jeju Island during 22-24 May were estimated to be from Zhejiang, Anhui and Fujian Provinces after 1-2 nights' flights. In the second series, it was estimated that FAW moths landed in southern Korea and Kyushu region of Japan simultaneously or successively during 5-9 June, and these moths mostly came from Guangdong and Fujian Provinces. The FAW moths in the third series were estimated to have immigrated from Taiwan Province onto Okinawa Islands during 19-24 June. During these migrations, southwesterly low-level jets extending from eastern China to southern Korea and/or Japan were observed in the northwestern periphery of the western Pacific Subtropical High. These results, for the first time, suggested that the overseas FAW immigrants invading Korea and Japan came from eastern and southern China. This study is helpful for future monitoring, early warning and the source control of this pest in the two countries.

Discovery of new macrophage M2 polarization modulators as multiple sclerosis treatment agents that enable the inflammation microenvironment remodeling.

The M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarization inhibition and ablated Akt1 inhibition activities. B9 has promising pharmacokinetic profiles, and significantly ameliorates the symptom and reduces demyelination in EAE mice. Moreover, the inflammation microenvironment is remodeled after B9 administration, with promoted M2-type macrophages and inhibited M1 polarization in the CNS and periphery, and suppressed the proinflammatory Th1 and Th17 cells responses. Therefore, the new macrophage M2 polarization modulator B9 could present a candidate for fulfilling the therapeutic strategies of MS.

Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma.

Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTK-PROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.

Design and synthesis of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives as novel GSK-3ß inhibitors and evaluation of their potential as multifunctional anti-Alzheimer agents.

Pleiotropic intervention has prominent advantages for complex pathomechanisms, such as Alzheimer's disease (AD). In this study, a series of novel 3-(4-pyridyl)-5-(4- sulfamido-phenyl)-1,2,4-oxadiazole derivatives were designed and synthesized following the multitarget-directed ligand-based strategy. All compounds were evaluated for glycogen synthase kinase 3ß (GSK-3ß) inhibition and antineuroinflammatory and neuroprotective activities. Given that abnormal glucose metabolism plays an important role in AD occurrence and development, the effects of all compounds on glucose consumption in HepG2 cells was evaluated. Compounds 5e and 10b showed good dual potency in GSK-3ß inhibition (IC50: 5e = 1.52 µM, 10b = 0.19 µM) and antineuroinflammatory potency (IC50: 5e = 0.47 ± 0.64 µM, 10b = 6.94 ± 2.33 µM). The effect of compound 10b on glucose consumption was higher than that of positive drug metformin. These compounds exerted a certain neuroprotective effect. Compound 10b dramatically reduced Aß-induced Tau hyperphosphorylation, thus inhibiting GSK-3ß at the cellular level. Notably, compounds 5e and 10b exhibited good inhibitory effects on the formation of intracellular reactive oxygen species (ROS). Moreover, these compounds displayed proper blood-brain barrier permeability and lacked neurotoxicity up to 50 µM concentration. Finally, in vivo experiments revealed that compound 10b improved cognitive impairment in scopolamine-induced mouse models. Results indicated that compound 10b deserves further study as a multifunctional lead compound.