Integrated multi-omics with machine learning to uncover the intricacies of kidney disease.

The development of omics technologies has driven a profound expansion in the scale of biological data and the increased complexity in internal dimensions, prompting the utilization of machine learning (ML) as a powerful toolkit for extracting knowledge and understanding underlying biological patterns. Kidney disease represents one of the major growing global health threats with intricate pathogenic mechanisms and a lack of precise molecular pathology-based therapeutic modalities. Accordingly, there is a need for advanced high-throughput approaches to capture implicit molecular features and complement current experiments and statistics. This review aims to delineate strategies for integrating multi-omics data with appropriate ML methods, highlighting key clinical translational scenarios, including predicting disease progression risks to improve medical decision-making, comprehensively understanding disease molecular mechanisms, and practical applications of image recognition in renal digital pathology. Examining the benefits and challenges of current integration efforts is expected to shed light on the complexity of kidney disease and advance clinical practice.

Neonatal exposure to sevoflurane induces adolescent neurobehavioral dysfunction by interfering with hippocampal glycerophoslipid metabolism in rats.

Sevoflurane exposure in the neonatal period causes long-term developmental neuropsychological dysfunction, including memory impairment and anxiety-like behaviors. However, the molecular mechanisms underlying such effects have not been fully elucidated. In this study, we investigated the effect of neonatal exposure to sevoflurane on neurobehavioral profiles in adolescent rats, and applied an integrated approach of lipidomics and proteomics to investigate the molecular network implicated in neurobehavioral dysfunction. We found that neonatal exposure to sevoflurane caused cognitive impairment and social behavior deficits in adolescent rats. Lipidomics analyses revealed that sevoflurane significantly remodeled hippocampal lipid metabolism, including lysophatidylcholine (LPC) metabolism, phospholipid carbon chain length and carbon chain saturation. Through a combined proteomics analysis, we found that neonatal exposure to sevoflurane significantly downregulated the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1), a key enzyme in the regulation of phospholipid metabolism, in the hippocampus of adolescent rats. Importantly, hippocampal LPCAT1 overexpression restored the dysregulated glycerophospholipid (GP) metabolism and alleviated the learning and memory deficits caused by sevoflurane. Collectively, our evidence that neonatal exposure to sevoflurane downregulates LPCAT1 expression and dysregulates GP metabolism in the hippocampus, which may contribute to the neurobehavioral dysfunction in the adolescent rats.

Glucocorticoid does not improve the renal prognosis of patients with diabetic nephropathy combined with acute tubulointerstitial nephritis: a retrospective analysis.

BACKGROUND AND OBJECTIVES: In clinical practice, some patients are diagnosed with diabetic nephropathy (DN) combined with acute tubulointerstitial nephritis (ATIN) through renal biopsy. There is relatively little research on the treatment and prognosis of such patients, and no consensus exists on the use of glucocorticoid for treatment. Therefore, our study explores the progression of DN combined with ATIN and the renal outcomes after treatment with glucocorticoid. METHODS: This study retrospectively analyzed patients diagnosed with DN combined with ATIN through renal biopsy at our center from January 1, 2015, to December 31, 2021. We collected general patient information, laboratory indicators, renal pathology indicators, and the glucocorticoid usage after kidney biopsy. Follow-up data were collected from medical records. Statistical analysis methods included t-tests, non-parametric tests, and chi-square tests. Univariate and multivariate Cox regression analyses were used to evaluate the risk factors for renal endpoint events in patients. Statistical significance was defined as p-values < 0.05. RESULTS: In this study, a total of 67 patients were included. The subjects were divided into two groups based on whether they received glucocorticoid treatment: 33 patients in the steroid group and 34 in the non-steroid group. In the steroid group, 19 patients reached the renal endpoint event, which was significantly higher than in the non-steroid group (57.58% vs. 29.41%, p = 0.038). Univariate Cox regression analysis showed that serum creatinine (HR = 1.008, p < 0.001), albumin (HR = 0.919, p < 0.001), 24-h urinary protein (HR = 1.093, p = 0.002), hemoglobin (HR = 0.964, p = 0.001), triglycerides (HR = 1.12, p = 0.04), and the use of glucocorticoid (HR = 2.507, p = 0.019) were influencing factors for renal endpoint events in patients with DN combined with ATIN. Multivariate Cox regression analysis showed that albumin (HR = 0.863, p = 0.003) was an independent risk factor for renal endpoint events in patients with DN combined with ATIN. CONCLUSIONS: The use of glucocorticoid in treatment does not improve renal prognosis in patients with DN combined with ATIN. Lower levels of albumin are associated with a worse renal prognosis.

Ferroptosis in Ischemic Stroke and Related Traditional Chinese Medicines.

Stroke is a severe neurological disorder resulting from the rupture or blockage of blood vessels, leading to significant mortality and disability worldwide. Among the different types of stroke, ischemic stroke (IS) is the most prevalent, accounting for 70-80% of cases. Cell death following IS occurs through various mechanisms, including apoptosis, necrosis, and ferroptosis. Ferroptosis, a recently identified form of regulated cell death characterized by iron overload and lipid peroxidation, was first described by Dixon in 2012. Currently, the only approved pharmacological treatment for IS is recombinant tissue plasminogen activator (rt-PA), which is limited by a narrow therapeutic window and often results in suboptimal outcomes. Recent research has identified several traditional Chinese medicines (TCMs) that can inhibit ferroptosis, thereby mitigating the damage caused by IS. This review provides an overview of stroke, the role of ferroptosis in IS, and the potential of certain TCMs to inhibit ferroptosis and contribute to stroke treatment.

Metabolism, Disposition, Excretion, and Potential Transporter Inhibition of 7-16, an Improving 5-HT2A Receptor Antagonist and Inverse Agonist for Parkinson's Disease.

Compound 7-16 was designed and synthesized in our previous study and was identified as a more potential selective 5-HT2A receptor antagonist and inverse agonist for treating Parkinson's disease psychosis (PDP). Then, the metabolism, disposition, and excretion properties of 7-16 and its potential inhibition on transporters were investigated in this study to highlight advancements in the understanding of its therapeutic mechanisms. The results indicate that a total of 10 metabolites of 7-16/[14C]7-16 were identified and determined in five species of liver microsomes and in rats using UPLC-Q Exactive high-resolution mass spectrometry combined with radioanalysis. Metabolites formed in human liver microsomes could be covered by animal species. 7-16 is mainly metabolized through mono-oxidation (M470-2) and N-demethylation (M440), and the CYP3A4 isozyme was responsible for both metabolic reactions. Based on the excretion data in bile and urine, the absorption rate of 7-16 was at least 74.7%. 7-16 had weak inhibition on P-glycoprotein and no effect on the transport activity of OATP1B1, OATP1B3, OAT1, OAT3, and OCT2 transporters. The comprehensive pharmacokinetic properties indicate that 7-16 deserves further development as a new treatment drug for PDP.

Discovery of Novel Antitumor Small-Molecule Agent with Dual Action of CDK2/p-RB and MDM2/p53.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

Integrated lipidomic and transcriptomic analysis reveals clarithromycin-induced alteration of glycerophospholipid metabolism in the cerebral cortex of mice.

Clarithromycin (CLA) has been widely used in the treatment of bacterial infection. Research reveals the adverse effects on the central nervous system among patients receiving CLA treatment; whereas, a relevant underlying mechanism remains considerably unclear. According to our research, an integrated lipidomic and transcriptomic analysis was applied to explore the effect of CLA on neurobehavior. CLA treatment caused anxiety-like behaviors dose-dependently during open field as well as elevated plus maze trials on mice. Transcriptomes and LC/MS-MS-based metabolomes were adopted for investigating how CLA affected lipidomic profiling as well as metabolic pathway of the cerebral cortex. CLA exposure greatly disturbed glycerophospholipid metabolism and the carbon chain length of fatty acids. By using whole transcriptome sequencing, we found that CLA significantly downregulated the mRNA expression of CEPT1 and CHPT1, two key enzymes involved in the synthesis of glycerophospholipids, supporting the findings from the lipidomic profiling. Also, CLA causes changes in neuronal morphology and function in vitro, which support the existing findings concerning neurobehavior in vivo. We speculate that altered glycerophospholipid metabolism may be involved in the neurobehavioral effect of CLA. Our findings contribute to understanding the mechanisms of CLA-induced adverse effects on the central nervous system. 1. Clarithromycin treatment caused anxiety-like behavior with dose-dependent response both in the open field and elevated plus maze test in mice; 2. Clarithromycin exposing predominately disturbed the metabolism of glycerophospholipids in the cerebral cortex of mice; 3. Clarithromycin application remarkably attenuated CEPT1 and CHPT1 gene expression, which participate in the last step in the synthesis of glycerophospholipids; 4. The altered glycerophospholipid metabolomics may be involved in the abnormal neurobehavior caused by clarithromycin.

Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1.

Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in cancer patients. However, no PLK1 inhibitor has been granted marketing approval until now. Therefore, more potentially promising PLK1 inhibitors need to be investigated. In this study, a series of novel inhibitors targeting PLK1 was designed and optimized derived from a new scaffold. After synthesis and characterization, we obtained the structure-activity relationship and led to the discovery of the most promising compound 30e for PLK1. The antiproliferative activity against HCT116 cells (IC50 = 5 nM versus 45 nM for onvansertib) and the cellular permeability and efflux ratio were significantly improved (PappA→B = 2.03 versus 0.345 and efflux ratio = 1.65 versus 94.7 for 30e and onvansertib, respectively). Further in vivo studies indicated that 30e had favorable antitumor activity with 116.2% tumor growth inhibition (TGI) in comparison with TGI of 43.0% for onvansertib. Furthermore, 30e improved volume of tumor tissue distribution in mice as compared to onvansertib. This initial study on 30e holds promise for further development of an antitumor agent.

Study on Pharmacokinetics and Metabolic Profiles of Novel Potential PLK-1 Inhibitors by UHPLC-MS/MS Combined with UHPLC-Q-Orbitrap/HRMS.

PLK-1 (Polo-like kinase-1) plays an essential role in cytokinesis, and its aberrant expression is considered to be keenly associated with a wide range of cancers. It has been selected as an appealing target and small-molecule inhibitors have been developed and studied in clinical trials. Unfortunately, most have been declared as failures due to the poor therapeutic response and off-target toxicity. In the present study, a novel potent PLK-1 inhibitor, compound 7a, was designed and synthetized. 1H NMR, 13C NMR, 19F NMR and mass spectrum were comprehensively used for the compound characterization. The compound exhibited higher potency against PLK-1 kinase, HCT-116 and NCI-H2030 cell lines than the positive control. Molecular docking indicated that the binding mode that the ATP binding site of PLK-1 was occupied by the compound. Then, a UHPLC-MS/MS method was established and validated to explore the pharmacokinetic behavior of the drug candidate. The method had good selectivity, high sensitivity and wide linearity. The exposure increased linearly with the dose, but the oral bioavailability was not satisfactory enough. Then, the metabolism was studied using liver microsomes by UHPLC-Q-Orbitrap/HRMS. Our research first studied the pharmacokinetic metabolic characteristics of 7a and may serve as a novel lead compound for the development of PLK-1 inhibitors.

4R Tau Modulates Cocaine-Associated Memory through Adult Dorsal Hippocampal Neurogenesis.

The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction.SIGNIFICANCE STATEMENT Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation. Here, we showed that Tau was significantly downregulated in the hippocampus in the cocaine memory formation. Tau knock-out (KO) promoted AHN in the hippocampal dentate gyrus (DG), resulting in the enhanced memory formation evoked by cocaine-cue stimuli. In contrast, genetically overexpressed 4R Tau in the hippocampus disrupted cocaine-cue memory by suppressing AHN. In addition, 4R Tau interacted directly with phosphoinositide 3-kinase (PI3K)-p85 and hindered its nuclear translocation, eventually repressing PI3K-AKT signaling, which is essential for hippocampal neuronal proliferation.

Efficacy, Safety, and Tolerability of Ansofaxine (LY03005) Extended-Release Tablet for Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding, Phase 2 Clinical Trial.

BACKGROUND: Ansofaxine (LY03005) extended-release tablet is a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. This study assessed the efficacy, safety, and appropriate dosage of ansofaxine for the treatment of major depressive disorder (MDD). METHODS: A multicenter, randomized, double-blind, placebo-controlled, dose-finding, Phase 2 clinical trial was conducted in China. Eligible patients with MDD (18-65 years) were randomly assigned to receive fixed-dose ansofaxine extended-release tablets (40, 80, 120, or 160 mg/d) or placebo for 6 weeks. The primary outcome measure was a change in the total score on the 17-item Hamilton Depression Rating Scale from baseline to week 6. RESULTS: A total of 260 patients were recruited from October 2015 to September 2017, and 255 patients received the study drug as follows: 40 mg (n = 52), 80 mg (n = 52), 120 mg (n = 51), and 160 mg (n = 51) ansofaxine and placebo (n = 49). Significant differences were found in mean changes in 17-item Hamilton Depression Rating Scale total scores at week 6 in the 4 ansofaxine groups vs placebo (-12.46; χ2 = -9.71, P = .0447). All doses of ansofaxine were generally well-tolerated. Treatment-related adverse events occurred in 141 patients (303 cases), yielding incidence rates of 51.92%, 65.38%, 56.86%, and 62.75% in the 40-, 80-, 120-, and 160-mg ansofaxine groups and 38.78% in the placebo group. CONCLUSION: Active doses (40, 80, 120, and 160 mg/d) of ansofaxine in a controlled setting were safe, tolerated, and effective in improving depression symptoms in MDD patients.

A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis.

Dysfunction of p53 is observed in many malignant tumors, which is related to cancer susceptibility. In cervical cancer, p53 is primarily degradated through the complex of high-risk human papillomaviruses (HPV) oncoprotein E6 and E6-associated protein (E6AP) ubiquitin ligase. What is less clear is the mechanism and role of murine double minute X (MDMX) in cervical carcinogenesis due to the inactive status of murine double minute 2 (MDM2). In the current study, XI-011 (NSC146109), a small-molecule inhibitor of MDMX, showed robust anti-proliferation activity against several cervical cancer cell lines. XI-011 promoted apoptosis of cervical cancer cells via stabilizing p53 and activating its transcription activity. Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-localized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical cancer.

mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1-GluA2 interaction in the nucleus accumbens.

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

The tyrosine kinase inhibitor LPM4870108 impairs learning and memory and induces transcriptomic and gene­specific DNA methylation changes in rats.

Tyrosine kinase inhibitors (TKIs), which have been developed and approved for cancer treatment in the last few years, are involved in synaptic plasticity of learning and memory. Epigenetic modifications also play crucial roles in the process of learning and memory, but its relationship with TKI-induced learning and memory impairment has not been investigated. We hypothesized that LPM4870108, an effective anti-cancer Trk inhibitor, might affect the learning and memory via epigenetic modifications. In this study, rats were orally administered with LPM4870108 (0, 1.25, 2.5, or 5.0 mg/kg) twice daily for 28 days, after which animals were subjected to a Morris water maze test. LPM4870108 exposure caused learning and memory impairments in this test in a dose-dependent manner and reduced the spine densities. Whole-genome transcriptomic analysis revealed significant differences in the patterns of hippocampal gene expression in LPM4870108-treated rats. These transcriptomic data were combined with next-generation bisulfite sequencing analysis, after which RT-PCR and pyrosequencing were conducted, revealing epigenetic alterations associated with genes (Snx8, Fgfr1, Dusp4, Vav2, and Satb2) known to regulate learning and memory. Increased mRNA and protein expression levels of hippocampal Dnmt1 and Dnmt3a were also observed in these rats. Overall, these data suggest that gene-specific alterations in patterns of DNA methylation can potentially contribute to the incidence of learning and memory deficits associated with exposure to LPM4870108.

PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor disorder associated with neuropathic pain model.

In view of postsynaptic density 95kDA (PSD95) tethers neuronal NO synthase (nNOS) to N-methyl-d-aspartate receptor (NMDAR), the PSD95-nNOS complex represents a therapeutic target of neuropathic pain. This study therefore sought to explore the ability of PCC-0105002, a novel PSD95-nNOS small molecule inhibitor, to alter pain sensitivity in rodent neuropathic pain models. Firstly, the IC50 of PCC-0105002 for PSD95 and NOS1 binding activity was determined using an Alpha Screen assay kit. Then, we examined the effects of PCC-0105002 in the mouse formalin test and in the rat spinal nerve ligation (SNL) model, and explored the ability of PCC-0105002 to mediate analgesia and to effect motor coordination in a rota-rod test. Moreover, the mechanisms whereby PCC-0105002 mediates analgesia was explored via western blotting, Golgi staining, and co-immunoprecipitation experiments in dorsal horn. The outcomes indicated that PCC-0105002 exhibited dose-dependent attenuation of phase II pain-associated behaviors in the formalin test. The result indicated that PCC-0105002 disrupted the PSD95-nNOS interaction with IC50 of 1.408 µM. In the SNL model, PCC-0105002 suppressed mechanical allodynia, thermal hyperalgesia, and abnormal dorsal horn wide dynamic range neuron discharge. PCC-0105002 mediated an analgesic effect comparable to that of MK-801, while it was better able to enhance motor coordination as compared with MK-801. Moreover, PCC-0105002 altered signaling downstream of NMDAR and thus functionally and structurally attenuating synaptic plasticity through respective regulation of the NR2B/GluR1/CaMKIIα and Rac1/RhoA pathways. These findings suggest that the novel PSD95-nNOS inhibitor PCC-0105002 is an effective agent for alleviating neuropathic pain, and that it produces fewer motor coordination-associated side effects than do NMDAR antagonists.

Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys.

LPM4870108 is a tropomyosin receptor kinase (Trk) inhibitor that is currently under consideration for human clinical trials. We characterized the toxicity and toxicokinetic properties of LPM4870108 following its oral administration to rhesus monkeys (5, 10, or 20 mg/kg/day for 4 weeks with a 4-week recovery period). No evidence of LPM4870108 toxicity was observed over this study as reflected by an absence of difference in body weight, ophthalmoscopy, urinalysis, gross, or histopathology findings. No significant differences in toxicity-related outcomes were detected when comparing LPM4870108 and control groups, and no significant treatment-related changes in food consumption, electrocardiogram results, blood pressure, hematological parameters, biochemical values, organ weight, or bone marrow parameters were observed. Treatment caused dose-dependent effects of gait disturbance, impaired balance, poor coordination, and decreased grip strength in all LPM4870108-treated animals, with these effects being attributable to excessive on-target Trk receptor inhibition. After the 4-week recovery period, all these abnormal treatment-related findings had fully or partially resolved. The toxicokinetic study of monkeys revealed that the LPM4870108 exposure increased with dose. Overall, LPM4870108 exhibited a safety profile in treated monkeys, indicating that the Highest Non-Severely Toxic Dose (HNSTD) for LPM4870108 in monkeys was 20 mg/kg/day.

Pharmacokinetics of S-epacadostat, an indoleamine 2,3-dioxygenase 1 inhibitor, in dog plasma and identification of its metabolites in vivo and in vitro.

S-epacadostat (S-EPA) is an efficient and selective small-molecule inhibitor of indoleamine 2,3-dioxygenase 1. It is an EPA analog with a sulfur atom instead of a nitrogen atom at the furazan C3 position. This study documents the pharmacokinetics of S-EPA in dogs and its metabolic pathway. After an oral administration of 15 mg/kg of S-EPA in dogs, the time to peak concentration was 0.80 h, the mean elimination half-life was 7.3 h, and the absolute bioavailability was 55.8%. Furthermore, we identified S-EPA metabolites in dog plasma and dog liver microsomes by UPLC-Q Exactive Orbitrap HRMS. In dog plasma, we found five metabolites, which came from glucuronidation (M1 and M2), deoxygenation (the amidine M4), glucuronidation of M4 (M3), and desulfonamidation and oxidation of M4 (the carboxylic acid M5). In dog liver microsomes, we identified three major metabolites, namely, the glucuronide conjugate (M6), a mono-oxidation product (M7), and a desulfonamidation and oxidation product (M8). Gut microbiota may cause the differences between in vivo and in vitro oxidation metabolisms. Contrary to EPA, S-EPA did not undergo dealkylation, suggesting that substituting the nitrogen with sulfur affects the metabolism of the adjacent alkyl side chain.

WITHDRAWN: PCC-0105002, a novel small molecule inhibitor of PSD95-nNOS protein-protein interactions, attenuates neuropathic pain and corrects motor coordination-associated side effects in neuropathic pain model.

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PCC0208023, a potent SHP2 allosteric inhibitor, imparts an antitumor effect against KRAS mutant colorectal cancer.

The non-receptor tyrosine phosphatase SHP2, encoded by PTPN11, plays an indispensable role in tumors driven by oncogenic KRAS mutations, which frequently occur in colorectal cancer. Here, PCC0208023, a potent SHP2 allosteric inhibitor, was synthesized to evaluate its inhibitory effects against the SHP2 enzyme, and the KRAS mutant colorectal cancer in vitro and in vivo, and its impart on the RAS/MAPK pathway. Consistent with an allosteric mode of inhibition, PCC0208023 can non-competitively inhibit the activity of full-length SHP2 enzyme, but lacks activity against the free catalytic domain of SHP2. Furthermore, PCC0208023 inhibited the proliferation of KRAS mutation-driven human colorectal cancer cells by inhibiting the RAS/MAPK signaling pathway in vitro. Importantly, PCC0208023 displayed good anti-tumor efficacy against KRAS-driven LS180 and HCT116 xenograft models in nude mice with the decreased Ki67 and p-ERK level, and increased cleaved caspase-3 expression in tumors. Interestingly, PCC0208023 maintained high levels in LS180 tumors within 24 h after administration and was mainly distributed in both intestines and lungs. Molecular docking studies revealed a higher affinity of PCC0208023 with key residues in the SHP2 allosteric pocket than RMC-4550. PCC0208023 deserves further optimization to identify additional low-toxic and potent SHP2 allosteric inhibitors with novel scaffolds for the treatment of patients with KRAS mutation-positive colorectal cancer.