ADCdb: the database of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a class of innovative biopharmaceutical drugs, which, via their antibody (mAb) component, deliver and release their potent warhead (a.k.a. payload) at the disease site, thereby simultaneously improving the efficacy of delivered therapy and reducing its off-target toxicity. To design ADCs of promising efficacy, it is crucial to have the critical data of pharma-information and biological activities for each ADC. However, no such database has been constructed yet. In this study, a database named ADCdb focusing on providing ADC information (especially its pharma-information and biological activities) from multiple perspectives was thus developed. Particularly, a total of 6572 ADCs (359 approved by FDA or in clinical trial pipeline, 501 in preclinical test, 819 with in-vivo testing data, 1868 with cell line/target testing data, 3025 without in-vivo/cell line/target testing data) together with their explicit pharma-information was collected and provided. Moreover, a total of 9171 literature-reported activities were discovered, which were identified from diverse clinical trial pipelines, model organisms, patient/cell-derived xenograft models, etc. Due to the significance of ADCs and their relevant data, this new database was expected to attract broad interests from diverse research fields of current biopharmaceutical drug discovery. The ADCdb is now publicly accessible at: https://idrblab.org/adcdb/.

ClusterX: a novel representation learning-based deep clustering framework for accurate visual inspection in virtual screening.

Molecular clustering analysis has been developed to facilitate visual inspection in the process of structure-based virtual screening. However, traditional methods based on molecular fingerprints or molecular descriptors limit the accuracy of selecting active hit compounds, which may be attributed to the lack of representations of receptor structural and protein-ligand interaction during the clustering. Here, a novel deep clustering framework named ClusterX is proposed to learn molecular representations of protein-ligand complexes and cluster the ligands. In ClusterX, the graph was used to represent the protein-ligand complex, and the joint optimisation can be used efficiently for learning the cluster-friendly features. Experiments on the KLIFs database show that the model can distinguish well between the binding modes of different kinase inhibitors. To validate the effectiveness of the model, the clustering results on the virtual screening dataset further demonstrated that ClusterX achieved better or more competitive performance against traditional methods, such as SIFt and extended connectivity fingerprints. This framework may provide a unique tool for clustering analysis and prove to assist computational medicinal chemists in visual decision-making.

TransFoxMol: predicting molecular property with focused attention.

Predicting the biological properties of molecules is crucial in computer-aided drug development, yet it's often impeded by data scarcity and imbalance in many practical applications. Existing approaches are based on self-supervised learning or 3D data and using an increasing number of parameters to improve performance. These approaches may not take full advantage of established chemical knowledge and could inadvertently introduce noise into the respective model. In this study, we introduce a more elegant transformer-based framework with focused attention for molecular representation (TransFoxMol) to improve the understanding of artificial intelligence (AI) of molecular structure property relationships. TransFoxMol incorporates a multi-scale 2D molecular environment into a graph neural network + Transformer module and uses prior chemical maps to obtain a more focused attention landscape compared to that obtained using existing approaches. Experimental results show that TransFoxMol achieves state-of-the-art performance on MoleculeNet benchmarks and surpasses the performance of baselines that use self-supervised learning or geometry-enhanced strategies on small-scale datasets. Subsequent analyses indicate that TransFoxMol's predictions are highly interpretable and the clever use of chemical knowledge enables AI to perceive molecules in a simple but rational way, enhancing performance.

Unveiling the protective role of sevoflurane in video-assisted thoracoscopic surgery associated-acute lung injury: Inhibition of ferroptosis.

Acute lung injury (ALI) frequently occurs after video-assisted thoracoscopic surgery (VATS). Ferroptosis is implicated in several lung diseases. Therefore, the disparate effects and underlying mechanisms of the two commonly used anesthetics (sevoflurane (Sev) and propofol) on VATS-induced ALI need to be clarified. In the present study, enrolled patients were randomly allocated to receive Sev (group S) or propofol anesthesia (group P). Intraoperative oxygenation, morphology of the lung tissue, expression of ZO-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), glutathione (GSH), Fe2+, glutathione peroxidase 4 (GPX4), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in the lung tissue as well as the expression of TNF-α and IL-6 in plasma were measured. Postoperative complications were recorded. Of the 85 initially screened patients scheduled for VATS, 62 were enrolled in either group S (n = 32) or P (n = 30). Compared with propofol, Sev substantially (1) improved intraoperative oxygenation; (2) relieved histopathological lung injury; (3) increased ZO-1 protein expression; (4) decreased the levels of TNF-α and IL-6 in both the lung tissue and plasma; (5) increased the contents of GSH and SOD but decreased Fe2+ concentration; (6) upregulated the protein expression of p-AKT, Nrf2, HO-1, and GPX4. No significant differences in the occurrence of postoperative outcomes were observed between both groups. In summary, Sev treatment, in comparison to propofol anesthesia, may suppress local lung and systemic inflammatory responses by activating the PI3K/Akt/Nrf2/HO-1 pathway and inhibiting ferroptosis. This cascade of effects contributes to the maintenance of pulmonary epithelial barrier permeability, alleviation of pulmonary injury, and enhancement of intraoperative oxygenation in patients undergoing VATS.

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.

Inhibition of TRIM32 by ibr-7 treatment sensitizes pancreatic cancer cells to gemcitabine via mTOR/p70S6K pathway.

Pancreatic cancer is one of the most notorious diseases for being asymptomatic at early stage and high mortality rate thereafter. However, either chemotherapy or targeted therapy has rarely achieved success in recent clinical trials for pancreatic cancer. Novel therapeutic regimens or agents are urgently in need. Ibr-7 is a novel derivative of ibrutinib, displaying superior antitumour activity in pancreatic cancer cells than ibrutinib. In vitro studies showed that ibr-7 greatly inhibited the proliferation of BxPC-3, SW1990, CFPAC-1 and AsPC-1 cells via the induction of mitochondrial-mediated apoptosis and substantial suppression of mTOR/p70S6K pathway. Moreover, ibr-7 was able to sensitize pancreatic cancer cells to gemcitabine through the efficient repression of TRIM32, which was positively correlated with the proliferation and invasiveness of pancreatic cancer cells. Additionally, knockdown of TRIM32 diminished mTOR/p70S6K activity in pancreatic cancer cells, indicating a positive feedback loop between TRIM32 and mTOR/p70S6K pathway. To conclude, this work preliminarily explored the role of TRIM32 in the malignant properties of pancreatic cancer cells and evaluated the possibility of targeting TRIM32 to enhance effectiveness of gemcitabine, thereby providing a novel therapeutic target for pancreatic cancer.

Design, synthesis and biological evaluation of new dihydropyridine derivatives as PD-L1 degraders for enhancing antitumor immunity.

Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.

Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors.

Fibroblast growth factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.

Identification of Novel Covalent XPO1 Inhibitors Based on a Hybrid Virtual Screening Strategy.

Nuclear export protein 1 (XPO1), a member of the nuclear export protein-p (Karyopherin-P) superfamily, regulates the transport of "cargo" proteins. To facilitate this important process, which is essential for cellular homeostasis, XPO1 must first recognize and bind the cargo proteins. To inhibit this process, small molecule inhibitors have been designed that inhibit XPO1 activity through covalent binding. However, the scaffolds for these inhibitors are very limited. While virtual screening may be used to expand the diversity of the XPO1 inhibitor skeleton, enormous computational resources would be required to accomplish this using traditional screening methods. In the present study, we report the development of a hybrid virtual screening workflow and its application in XPO1 covalent inhibitor screening. After screening, several promising XPO1 covalent molecules were obtained. Of these, compound 8 performed well in both tumor cell proliferation assays and a nuclear export inhibition assay. In addition, molecular dynamics simulations were performed to provide information on the mode of interaction of compound 8 with XPO1. This research has identified a promising new scaffold for XPO1 inhibitors, and it demonstrates an effective and resource-saving workflow for identifying new covalent inhibitors.

Identification of new IDH2R140Q inhibitors by discriminatory analysis-based molecular docking and biological evaluation.

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2R140Q inhibitors with moderate-to-good IC50 values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild-type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5-a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2R140Q , providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.

A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells.

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 µM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

Genomic sequencing, genome-scale metabolic network reconstruction, and in silico flux analysis of the grape endophytic fungus Alternaria sp. MG1.

BACKGROUND: Alternaria sp. MG1, an endophytic fungus isolated from grape, is a native producer of resveratrol, which has important application potential. However, the metabolic characteristics and physiological behavior of MG1 still remains mostly unraveled. In addition, the resveratrol production of the strain is low. Thus, the whole-genome sequencing is highly required for elucidating the resveratrol biosynthesis pathway. Furthermore, the metabolic network model of MG1 was constructed to provide a computational guided approach for improving the yield of resveratrol. RESULTS: Firstly, a draft genomic sequence of MG1 was generated with a size of 34.7 Mbp and a GC content of 50.96%. Genome annotation indicated that MG1 possessed complete biosynthesis pathways for stilbenoids, flavonoids, and lignins. Eight secondary metabolites involved in these pathways were detected by GC-MS analysis, confirming the metabolic diversity of MG1. Furthermore, the first genome-scale metabolic network of Alternaria sp. MG1 (named iYL1539) was reconstructed, accounting for 1539 genes, 2231 metabolites, and 2255 reactions. The model was validated qualitatively and quantitatively by comparing the in silico simulation with experimental data, and the results showed a high consistency. In iYL1539, 56 genes were identified as growth essential in rich medium. According to constraint-based analysis, the importance of cofactors for the resveratrol biosynthesis was successfully demonstrated. Ethanol addition was predicted in silico to be an effective method to improve resveratrol production by strengthening acetyl-CoA synthesis and pentose phosphate pathway, and was verified experimentally with a 26.31% increase of resveratrol. Finally, 6 genes were identified as potential targets for resveratrol over-production by the recently developed methodology. The target-genes were validated using salicylic acid as elicitor, leading to an increase of resveratrol yield by 33.32% and the expression of gene 4CL and CHS by 1.8- and 1.6-fold, respectively. CONCLUSIONS: This study details the diverse capability and key genes of Alternaria sp. MG1 to produce multiple secondary metabolites. The first model of the species Alternaria was constructed, providing an overall understanding of the physiological behavior and metabolic characteristics of MG1. The model is a highly useful tool for enhancing productivity by rational design of the metabolic pathway for resveratrol and other secondary metabolites.

Compartmentalization of Incompatible Polymers within Metal-Organic Frameworks towards Homogenization of Heterogeneous Hybrid Catalysts for Tandem Reactions.

New catalytic systems that contain incompatible catalytic sites were constructed by the in situ polymerization of acidic and basic polymers into metal-organic frameworks, which resulted in highly porous, recyclable, and durable catalytic composites with excellent compartmentalization, so that opposing agents were spatially isolated. These synthesized hybrid catalysts exhibited excellent catalytic activity for one-pot "wolf and lamb" reactions (deacetalization/Knoevenagel or Henry), which was attributed to their unique characteristic of having a locally homogeneous, but globally heterogeneous, structure.

Comparison of pinoresinol diglucoside production by Phomopsis sp. XP-8 in different media and the characterisation and product profiles of the cultivation in mung bean.

BACKGROUND: Phomopsis sp. XP-8 is an endophytic fungus with the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application in biosynthesis of PDG independent of plants. In order to enhance the production of PDG, 18 different natural materials were tested in solid-state cultivation of Phomopsis sp. XP-8. RESULTS: Most of the tested natural materials promoted the production of PDG. A supplement derived from mung beans produced the highest PDG yield and better fungal growth than the other materials. Also, pinoresinol monoglucoside, pinoresinol and other substrates (phenylalanine, p-coumaric acid, cinnamic acid, caffeic acid, and ferulic acid) were obtained after fermentation on mung beans. Furthermore, PDG production was much higher when mung beans were incorporated into solid state agar versus a liquid medium. The highest pinoresinol diglucoside production (72.1 mg kg(-1) in fresh culture) was obtained in 9 days using a solid state culture of Phomopsis sp. XP-8 on a mung bean grain medium containing 100 g kg(-1) glucose. Mung bean water-soluble polysaccharide was identified as a major promoter of PDG production by Phomopsis sp. XP-8. CONCLUSION: Mung bean, especially its water-soluble polysaccharide fraction, was an efficient natural material to promote PDG production by Phomopsis sp. XP-8. © 2015 Society of Chemical Industry.

Production of pinoresinol diglucoside, pinoresinol monoglucoside, and pinoresinol by Phomopsis sp. XP-8 using mung bean and its major components.

Phomopsis sp. XP-8 is an endophytic fungus that has the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application for the biosynthesis of PDG independent of plants. When cultivated in mung bean medium, PDG production was significantly improved and pinoresinol monoglucoside (PMG) and pinoresinol (Pin) were also found in the culture medium. In this experiment, starch, protein, and polysaccharides were isolated from mung beans and separately used as the sole substrate in order to explore the mechanism of fermentation and identify the major substrates that attributed to the biotransformation of PDG, PMG, and Pin. The production of PDG, PMG, and Pin was monitored using high-performance liquid chromatography (HPLC) and confirmed using HPLC-MS. Activities of related enzymes, including phenylalanine ammonia-lyase (PAL), trans-cinnamate 4-hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL) were analyzed and tracked during the cultivation. The reaction system contained the compounds isolated from mung bean in the designed amount. Accumulation of phenylalanine, cinnamic acid, p-coumaric acid, PDG, PMG, and Pin and the activities of PAL, C4H, and 4CL were measured during the bioconversion. PMG was found only when mung bean polysaccharide was analyzed, while production of PDG and Pin were found when both polysaccharide and starch were analyzed. After examining the monosaccharide composition of the mung bean polysaccharide and the effect of the different monosaccharides had on the production of PMG, PDG, and Pin, galactose in mung bean polysaccharide proved to be the major factor that stimulates the production of PMG.

Alkenyl/thiol-derived metal-organic frameworks (MOFs) by means of postsynthetic modification for effective mercury adsorption.

The synthesis of new functionally diverse alkenyl-derived Cr-MIL-101s (MIL=material of Institute Lavoisier) was realized by a novel and convenient postsynthetic modification (PSM) protocol by means of the carbon-carbon bond-forming Mizoroki-Heck reaction. The new PSM protocol demonstrates a broad scope of substrates with excellent tolerance of functionality under mild reaction conditions. Moreover, a new metal-organic framework (MOF) that bears both alkenyl and thiol side chains prepared by means of the tandem PSM method has shown excellent adsorbent ability in removing mercury ions from water.

Integration of covalent organic frameworks and molecularly imprinted polymers for selective extraction of flavonoid naringenin from grapefruit (Citrus × paradisi Macf.) peels.

Grapefruit (Citrus × paradisi Macf.) peel, a by-product of the citrus-processing industry, possesses an important economic value due to the richness of bioactive compounds. In this study, boron-linked covalent organic frameworks integrated with molecularly imprinted polymers (CMIPs) were developed via a facile one-pot bulk polymerization approach for the selective extraction of naringenin from grapefruit peel extract. The obtained CMIPs possessed a three-dimensional network structure with uniform pore size distribution, large surface areas (476 m2/g), and high crystallinity. Benefiting from the hybrid functional monomer APTES-MAA, the acylamino group can coordinate with the boronate ligands of the boroxine-based framework to form B-N bands, facilitating the integration of imprinted cavities with the aromatic skeleton. The composite materials exhibited a high adsorption capacity of 153.65 mg/g, and a short adsorption equilibrium time of 30 min for naringenin, together with favorable selectivity towards other flavonoid analogues. Additionally, the CMIPs captured the template molecules through π-π* interaction and hydrogen bonding, as verified by FT-IR and XPS. Furthermore, they had good performance when employed to enrich naringenin in grapefruit peels extract compared with the common adsorbent materials including AB-8, D101, cationic exchange resin, and active carbon. This research highlights the potential of CMIPs composite materials as a promising alternative adsorbent for naringenin extraction from grapefruit peel.

Recent progress and applications of small molecule inhibitors of Keap1-Nrf2 axis for neurodegenerative diseases.

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a crucial regulator against oxidative stress (OS) damage in various cells and organs. It has garnered significant attention as a potential therapeutic target for neurodegenerative diseases (NDD). Although progress has been achieved in strategies to regulate the Keap1-Nrf2 pathway, the availability of Nrf2 activators applicable to NDD is currently limited. Currently, the FDA has approved the Nrf2 activators dimethyl fumarate (DMF) and Omaveloxolone (Omav) as novel first-line oral drugs for the treatment of patients with relapsing forms of multiple sclerosis and Friedreich's ataxia. A promising alternative approach involves the direct inhibition of Keap1-Nrf2 protein-protein interactions (PPI), which offers numerous advantages over the use of electrophilic Nrf2 activators, primarily in avoiding off-target effects. This review examines the compelling evidence supporting the beneficial role of Nrf2 in NDD and explores the potential of Keap1 inhibitors and Keap1-Nrf2 PPI inhibitors as therapeutic agents, with the aim to provide further insights into the development of inhibitors targeting this pathway for the treatment of NDD.

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.