Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

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.

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.

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

NF-κB inducing kinase (NIK) is a key regulator in the noncanonical nuclear factor κB cells (NF-κB) signaling pathway. Dysregulation of NIK is often related with autoimmune disorders and malignancies. However, the number of reported NIK inhibitors is scarce. Discriminatory analysis-based molecular docking was used to examine the accuracy of the binding conformation and to estimate the binding affinity, leading to the identification of several new NIK inhibitors with moderate IC50 (ranging from 48.9 to 103.4 µM). Among them, compound 5, the most potent one (IC50 48.9 ± 6.9 µM), also showed moderate antiproliferation activity against cancer SW1990 cells, with an IC50 value of 20.1 ± 6.0 µM. Further dynamic simulations were performed to provide more in-depth details on the binding conformation of compound 5 and the NIK protein, providing some structural clues for further optimization of compound 5 as a novel NIK inhibitor.

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.

Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors.

A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1 µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50 = 21 nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti-proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy.

Design and synthesis of novel hydroxypyridinone derivatives as potential tyrosinase inhibitors.

Two groups of novel hydroxypyridinone derivatives 6(a-e) and 12(a-c), were designed as potential tyrosinase inhibitors, and synthesized using kojic acid as a starting material. The tyrosinase inhibitory activity of these two groups was demonstrated to be potent, especially compounds 6e and 12a, whose IC50 values for monophenolase activity were 1.95µM and 2.79µM, respectively. Both of these values are lower than that of kojic acid (IC50=12.50µM). Compounds 6e and 12a were investigated for the inhibitory effect on diphenolase activity. The results showed that the inhibitory mechanism of these two compounds was reversible and that the inhibitory type was a competitive-uncompetitive mixed-type. The values of IC50 of 6e and 12a on the diphenolase activity of tyrosinase were determined to be 8.97µM and 26.20µM, respectively. The inhibitory constants (KI and KIS) of 6e were determined as 17.17µM and 22.09µM, respectively; and the KI and KIS values of 12a were 34.41µM and 79.02µM, respectively. Compound 6e showed a greater ability to reduce copper and a stronger copper chelating ability than kojic acid.

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.

Pancreatitis and Pancreatic Cancer Risk.

Purpose: The present retrospective study aimed to explore the relationship between pancreatitis and pancreatic cancer in the population cohort of the UK Biobank (UKB) (https://www.ukbiobank.ac.uk). Methods: From the 500 thousand population cohort of UKB, according to the age and gender of patients with pancreatic cancer 1:10, matching the control without pancreatic cancer, the binary Logistic regression model was used to analyze the relationship between pancreatitis and pancreatic cancer, and subgroup analyses were used to identify potential effect modifiers. Results: A total of 1538 patients with pancreatic cancer were compared with 15 380 controls. In the fully adjusted model, patients with pancreatitis had a significantly increased risk of pancreatic cancer compared with no pancreatitis. The risk of pancreatitis and pancreatic cancer increased with the age of pancreatitis, and the risk of pancreatic cancer was highest in the 61 to 70 age group. In addition, in the first 3 years of acute pancreatitis, the risk of pancreatic cancer increased significantly with the increase in the duration of the disease (odds ratio [OR] 29.13, 95% confidence interval [CI]: 16.34-51.93), after 3 years, the trend of increase decreased. After more than 10 years, there was no significant correlation between the risk of acute pancreatitis and pancreatic cancer. However, patients with chronic pancreatitis were significantly associated with an increased risk of pancreatic cancer only in the first 3 years (OR 28.14, 95% CI: 14.86-53.31). Conclusion: Pancreatitis may associate with an increased risk of pancreatic cancer. The older the age of pancreatitis, the higher the risk of pancreatic cancer. The risk of pancreatic cancer increases significantly in the first 3 years of the course of pancreatitis. This may provide an alternative strategy for the early identification of individuals at high risk of pancreatic cancer.

[Method for screening cysteinyl leukotriene receptor 2 antagonists and preliminary screening of compounds].

OBJECTIVE: To establish a method for screening cysteinyl leukotriene receptor 2 (CysLT(2)) antagonists and to preliminarily screen a series of synthetic compounds. METHODS: Rat glioma cell line (C6 cells) highly expressing CysLT(2) receptor was used. Intracellular calcium concentration was measured after stimulation with the agonist LTD(4),which was used to screen compounds with antagonist activity for CysLT(2) receptor. Bay u9773, a CysLT1/CysLT(2) receptor non-selective antagonist, and AP-100984, a CysLT(2) receptor antagonist, were used as control. RESULT: PT-PCR showed a higher expression of CysLT(2) receptor in C6 cells. LTD(4) at 1 mumol/L significantly increased intracellular calcium in C6 cells; the maximal effect was about 37.5% of ATP, a positive stimulus.LTD(4)-induced increase of intracellular calcium was blocked by CysLT(2) receptor antagonists, but not by CysLT(1) receptor antagonists. Among the synthetic compounds, D(XW-)1,2,13,23,29 and 30 inhibited LTD(4)-induced increase of intracellular calcium. CONCLUSION: LTD(4)-induced change in intracellular calcium in C6 cells can be used as a screening method for CysLT(2) receptor antagonists. The compounds, D(XW-)1,2,13,23,29 and 30, possess antagonist activity for CysLT(2) receptor.

Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles.

The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.

Bicyclo[2.2.1]heptane containing N,N'-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents.

CXCR1 and CXCR2 are CXC chemokine receptors (CXCRs), corresponding to cytokines of the CXC chemokine family. CXCR2 was found to be 77% homologous to CXCR1. Antagonism of the chemokine receptor CXCR2 has been proposed as a new strategy for the treatment of metastatic cancer. In order to find a CXCR2 selective antagonist, a bicyclo[2.2.1]heptane containing N,N'-diarylsquaramide (compound 2e) was identified by introducing a bridge ring system into the N,N'-diarylsquaramide skeleton, and it exhibited good CXCR2 antagonistic activity (CXCR2IC50 = 48 nM) and good selectivity (CXCR1IC50/CXCR2IC50 = 60.4). Furthermore, an in vitro biological assay of compound 2e also demonstrated its good anti-cancer metastatic effect against the pancreatic cancer cell line CFPAC1. In addition, compound 2e showed an extremely high stability in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF), as well as in rat and human plasma, but not in rat and human liver microsomes. In vivo pharmacokinetic studies in rats indicated that 2e has an excellent PK profile (10 mg kg-1 po, C max = 2863 ng mL-1, t 1/2 = 2.58 h). Moreover, molecular docking was further implemented to propose the preponderant configuration of compound 2e, providing important and useful guidelines for further development.

Novel hydroxypyridinone derivatives containing an oxime ether moiety: Synthesis, inhibition on mushroom tyrosinase and application in anti-browning of fresh-cut apples.

A range of hydroxypyridinone derivatives were synthesized starting from kojic acid. Among them, 10 and 11 were found to possess the strongest inhibitory effect on monophenolase activity of mushroom tyrosinase, having IC50 values of 2.04 and 1.60µM, respectively. The IC50 values of 10 and 11 for the inhibition of diphenolase activity of mushroom tyrosinase were determined as 13.89 and 7.99µM, respectively. Investigation of the inhibitory mechanism of these two compounds indicated that the inhibition was reversible and of a competitive-uncompetitive mixed type. The KI and KIS values of 10 were determined to be 24.84 and 32.54µM, respectively, and the corresponding values for 11 being 18.07 and 21.34µM, respectively. The effect of 11 on the browning process of fresh-cut apples was evaluated by measuring the color change and browning index. The results indicated that 11 had a significant effect on controlling the browning of fresh-cut apple slices.

Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-RafV600E inhibitors.

A set of ninety-eight B-RafV600E inhibitors was used for the development of a molecular docking based QSAR model using linear and non-linear regression models. The integration of docking scores and key interaction profiles significantly improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.935, Rtest2 = 0.728 and QCV2 = 0.905). The established MD-SVR (molecular docking based SMV regression) model as well as model screening of a natural product database was carried out and two natural products (quercetin and myricetin) with good prediction activities were biologically evaluated. Both compounds exhibited promising B-RafV600E inhibitory activities (ICQuercetin50 = 7.59 µM and ICMyricetin50 = 1.56 µM), suggesting a high reliability and good applicability of the established MD-SVR model in the future development of B-RafV600E inhibitors with high efficacy.

Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping.

Succinate dehydrogenase (SDH) has been demonstrated as a promising target for fungicide discovery. Crystal structure data have indicated that the carboxyl "core" of current SDH inhibitors contributed largely to their binding affinity. Thus, identifying novel carboxyl "core" SDH inhibitors would remarkably improve the biological potency of current SDHI fungicides. Herein, we report the discovery and optimization of novel carboxyl scaffold SDH inhibitor via the integration of in silico library design and a highly specific amide feature-based pharmacophore model. To our delight, a promising SDH inhibitor, A16c (IC50 = 1.07 µM), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50 = 11.0 µM) and improved potency against Sclerotinia sclerotiorum (EC50 = 5.5 µM) and Phyricularia grisea (EC50 = 12.0 µM) in comparison with the positive control thifluzamide, with EC50 values of 0.09, 33.2, and 33.4 µM, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors.

Design, Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole-pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors.

The identification of novel succinate dehydrogenase (SDH) inhibitors represents one of the most attractive directions in the field of fungicide research and development. During our continuous efforts to pursue inhibitors belonging to this class, some structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been discovered via the introduction of scaffold hopping and bioisosterism to compound 1, a remarkably potent lead obtained by pharmacophore-based virtual screening. As a result of the evaluation against three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani, and Pyricularia grisea, a majority of them displayed potent fungicidal activities. In particular, compounds 12I-i, 12III-f, and 12III-o exhibited excellent fungicidal activity against S. sclerotiorum and R. solani comparable to that of commercial SDHI thifluzamide and 1.

A Copper-Catalyzed Tandem Cyclization Reaction of Aminoalkynes with Alkynes for the Construction of Tetrahydropyrrolo[1,2-a]quinolines Scaffold.

A synthetic method for diversely substituted tetrahydropyrrolo[1,2-a]quinolines was developed via CuCl-catalyzed cascade transformation of internal aminoalkynes with alkynes under microwave- irradiation.

Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings.

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8-11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.

Straightforward installation of carbon-halogen, carbon-oxygen and carbon-carbon bonds within metal-organic frameworks (MOF) via palladium-catalysed direct C-H functionalization.

The straightforward C-H functionalization of UiO-67-dcppy materials was realized by a Pd-catalysed PSM. This novel protocol provides an efficient method for the synthesis of various functionalized MOFs, which have shown promising adsorbent ability in removing phenolic contaminates from water.