SHP2 Inhibitor Research Articles

Optimization of SHP2 allosteric inhibitors with novel tail heterocycles and their potential as antitumor therapeutics

SHP2, a non-receptor protein tyrosine phosphatase involved in cancers, plays a pivotal role in numerous cellular signaling cascades, including the MAPK and PD-L1/PD-1 pathways. Although several SHP2 allosteric inhibitors have already entered clinical trials, none have been approved to date. Therefore, the development of new SHP2 allosteric inhibitors with improved efficacy is urgently required. Herein, we report the optimization of tail heterocycles in SHP2 allosteric inhibitors using a structure-based drug design strategy. Four series of compounds with different tail skeletons were synthesized, among which D13 showed notable inhibitory activity (IC50 = 1.2 μM) against SHP2. Molecular docking and binding studies indicated that the newly synthesized compounds exerted enzymatic inhibitory effects by directly binding to SHP2 with relatively slow dissociation rates. At the cellular level, Huh7 cells demonstrated heightened sensitivity to the novel SHP2 inhibitors, and D13 exhibited superior antiproliferative activity (IC50 = 38 μM) by arresting G0/G1 cell cycle, facilitating cell apoptosis and suppressing the MAPK signaling pathway. In the in vivo study, D13 displayed significant antitumor activity in a Huh7 xenograft model and possessed favorable druggability with acceptable oral bioavailability (F = 54 %) and half-life (t1/2 = 10.57 h). Collectively, this study lays a robust foundation for further optimization of the tail heterocycle skeleton in SHP2 allosteric inhibitors.

Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm

SHP2-E76K, a mutant encoded by the PTPN11 gene, was associated with various solid tumors, such as lung cancer, glioblastoma, and intellectual disability. SHP2-E76K has become potential drug targets, while there was no effective inhibitor against the mutant currently. At present, the crystal complex structure of SHP099 with SHP2-E76K has been reported in the RCSB PDB protein data bank, however, the dynamic structure of SHP099 binding to the active center of SHP2-E76K protein was still lacking. Therefore, this study used molecular dynamics simulation and Markov model to characterize the kinetics of the inhibitor SHP099 with SHP2-E76K enzyme and to determine the active binding site, which would give a hint of a vital enzyme-substrate interaction in atomistic detail that proposed the potential to be applied for the discovery of more effective SHP2-E76K inhibitors and, in broader terms, dynamic protein-drug interactions.

Baliosperoid A attenuates lipopolysaccharide-induced acute lung injury by targeting SHP2 to inhibit inflammation and oxidative stress

Acute lung injury (ALI) remains a devastating clinical condition with limited therapeutic options. While Src homology-2 domain-containing protein tyrosine phosphatase 2 (SHP2) has emerged as a critical mediator in ALI pathogenesis, effective SHP2-targeting therapeutics remain largely elusive. Baliospermum solanifolium (Burm.) is a traditional medicine used to treat various diseases such as asthma, edema, bronchitis, jaundice, and constipation. Baliosperoid A (BA), a diterpenoid compound derived from Baliospermum solanifolium’s roots, exhibits potent NO inhibitory activity in RAW264.7 cells. However, its anti-inflammatory activity and potential targets have never been reported. Here, we report BA acts as a selective SHP2 inhibitor with remarkable therapeutic potential against ALI. Through comprehensive molecular and functional analyses, we demonstrate that BA directly binds to and inhibits SHP2 phosphatase activity with high specificity (IC50 = 1.638 ± 0.324 μM). Mechanistically, BA orchestrates a dual-action therapeutic effect by simultaneously suppressing inflammatory cascades through SHP2-mediated MAPK and NF-κB pathway inhibition while activating the Nrf2-dependent antioxidant response. In preclinical models of ALI and sepsis, BA treatment significantly improved survival rates, preserved lung architecture, and prevented multi-organ dysfunction. Notably, BA demonstrated superior efficacy to the existing SHP2 inhibitor SHP099, particularly in sepsis survival outcomes (90 % vs 50 % survival at 24 h). Our findings not only identify BA as a promising therapeutic candidate for ALI but also establish a novel paradigm for targeting SHP2 in inflammatory diseases.

Previously Published Phosphatase Probes have Limited Utility Due to their Unspecific Reactivity.

This study explores the use of activity-based protein profiling to study protein tyrosine phosphatases. With the discovery of allosteric SHP2 inhibitors, this enzyme family has resurfaced as interesting drug targets. Therefore, we envisioned that previously described direct electrophiles and quinone methide-based traps targeting phosphatases could be applied in competitive activity-based protein profiling assays. This study evaluates three direct electrophiles, specifically, a vinyl sulfonate, a vinyl sulfone, and an α-bromobenzylphosphonate as well as three quinone methide-based traps as activity-based probes. For all these moieties it was previously shown that they could selectively engage in assays with purified or overexpressed phosphatases in bacterial lysates. However, this study demonstrates that probes based on these moieties all suffer from unspecific labelling. Direct electrophiles were either unspecific or not activity-based, while quinone methide-based traps showed dependence on phosphatase activity but also resulted in unspecific labelling due to diffusion after activation. This phenomenon, termed 'bystander' labelling, occurred even with catalytically inactive SHP2 mutants. We concluded that alternative strategies or chemistries are needed to apply activity-based protein profiling in phosphatase research. Moreover, this study shows that quinone methide-based designs have limited potential in probe and inhibitor development strategies due to their intrinsic reactivity.

TNO155 is a selective SHP2 inhibitor to target PTPN11-dependent oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is known to be driven by multiple intricated receptor tyrosine kinases (RTKs) including EGFR, PI3K/AKT and MAPK signaling pathways. However, whilst targeting EGFR with cetuximab has been approved for the treatment of OSCC, other single-agent inhibitors of the RTKs have shown modest effects in improving survival. From the genome-wide CRISPR/Cas9 screen on 21 OSCC cell lines, we have identified PTPN11 among the top essential genes in OSCC. PTPN11 encodes for SHP2, a phosphatase that acts as a master signal transducer, downstream of various RTKs. Although PTPN11 overexpression has been reported in OSCC, little is known about its role as an essential gene for OSCC survival and its potential as a therapeutic target. Herein, we confirmed that PTPN11 is an essential gene in OSCC where its deletion significantly impacted cell survival. We evaluated three SHP2 inhibitors on 21 OSCC cell lines and found TNO155 to be significantly associated with CRISPR dependency score. We showed that TNO155 caused dose-dependent suppression on p-ERK and p-MEK, and suppresses the JAK/STAT pathway via downregulating p-JAK1, p-STAT1, p-STAT3. Furthermore, we confirmed that the combination of the mTOR inhibitor, everolimus with TNO155 is synergistic in OSCC. In summary, PTPN11 is a promising therapeutic target in OSCC that can be selectively targeted by SHP2 inhibitor such as TNO155. Our findings on the use of mTOR inhibitor, everolimus to overcome resistance to TNO155 are essential to inform on next phases of clinical trials which is warranted for the treatment of OSCC.

Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade

Mutant selective drugs targeting the inactive, GDP-bound form of KRASG12C have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RASG12C in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.

Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis.

Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in chronic obstructive pulmonary disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. In this study, we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage "eat me" signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are associated with CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and inhibition of the accumulation and phosphorylation of cytoskeleton-regulating nonmuscle myosin IIa. This inhibition of innate immune responses such as phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases such as COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell costimulation, and regulate a number of other oncogenic and inflammation pathways suggests that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD, and other disorders.

SHP2 ablation mitigates osteoarthritic cartilage degeneration by promoting chondrocyte anabolism through SOX9.

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4+ AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan+ pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.

19Fluorine-MRI Based Longitudinal Immuno-Microenvironment-Monitoring for Pancreatic Cancer.

Pancreatic cancer has a poor prognosis. Targeting Kirsten Rat Sarcoma (KRAS) mutation and its related pathways may enhance immunotherapy efficacy. While in vivo monitoring of therapeutic response and immune cell migration remains challenging, Fluorine-19 MRI (19F MRI) may allow noninvasive longitudinal imaging of immune cells. Evaluating the potential of 19F MRI for monitoring changes in the tumor immune microenvironment, in response to combined SHP2/MEK inhibition. Pre-clinical animal study. Murine genetically engineered pancreatic cancer model (N = 20, both sexes). 9.4-T, two-dimensional multi-slice Rapid Acquisition with Relaxation Enhancement sequence. Intravenous injection of 19F-perfluorocarbon (PFC) nanoparticles. Upon tumor detection by conventional 1H MRI screening, 19F MRI was performed in mice 24 hours after PFC nanoparticle administration. Animals were randomly assigned to four treatment groups: allosteric Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) inhibitor SHP099, the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor Trametinib, the combination of both, or a vehicle control (4 to 6 mice each group), administered every other day per oral gavage. 1H and 19F MRI was repeated 7 days and 14 days later. Pancreatic immune cell infiltrates were analyzed by flow cytometry and multiplex immunohistofluorescence (mIHF) upon sacrifice. Independent t-tests and one-way analysis of variance. 19F MRI revealed continuous decrease of PFC-signals in tumors from vehicle controls (100%, 80%, and 74% on days 0, 7, and 14, respectively), contrasting with stable or increasing signals under KRAS-pathway-directed treatment. MEK inhibition showed 100%, 152%, and 84% and dual SHP2/MEK1/2 inhibition demonstrated signals of 100%, 134%, and 100% on days 0, 7, 14, respectively. mIHF analyses indicated CD11b+ macrophages/monocytes as primary contributors to the observed 19F MRI signal differences. 19F MRI might provide non-invasive longitudinal estimates for abundance and spatial distribution of CD11b+ macrophages/monocytes in pancreatic cancer. 1 TECHNICAL EFFICACY: Stage 2.

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Design, Synthesis and Antitumor Activity of a Novel Class of SHP2 Allosteric Inhibitors with a Furanyl Amide-Based Scaffold.

SHP2 plays a critical role in modulating tumor growth and PD-1-related signaling pathway, thereby serving as an attractive antitumor target. To date, no antitumor drugs targeting SHP2 have been approved, and hence, the search of SHP2 inhibitors with new chemical scaffolds is urgently needed. Herein, we developed a novel SHP2 allosteric inhibitor SDUY038 with a furanyl amide scaffold, demonstrating potent binding affinity (KD = 0.29 μM), enzymatic activity (IC50 = 1.2 μM) and similar binding interactions to SHP099. At the cellular level, SDUY038 exhibited pan-antitumor activity (IC50 = 7-24 μM) by suppressing pERK expression. Furthermore, SDUY038 significantly inhibited tumor growth in both xenograft and organoid models. Additionally, SDUY038 displayed acceptable bioavailability (F = 14%) and half-life time (t1/2 = 3.95 h). Conclusively, this study introduces the furanyl amide scaffold as a novel class of SHP2 allosteric inhibitors, offering promising lead compounds for further development of new antitumor therapies targeting SHP2.

WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer

Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.

Mechanistic study of inhibitory peptides with SHP-1 in hypertonic environment for infection model

Cutaneous Leishmaniasis, an infectious disease is globally the most prevalent form of leishmaniasis accounting for approximately 1 million cases every year as per world health organization. Infected individuals develop skin lesion which has been reported to be infiltrated by immune cells and parasite with high sodium accumulation creating hypertonic environment. In our work, we tried to mimic the hypertonic environment in virtual environment to study dynamicity of SHP-1 and NFAT5 along with their interactions through molecular dynamics simulation. We validated the SHP-1 and NFAT5 dynamics in infection and HSD conditions to study the impact of hypertonicity derived NFAT5 mediated response to L.major infection. We also evaluated our therapeutic peptides for their binding to SHP-1 and to form stable complex. Membrane stability with the peptides was analyzed to understand their ability to sustain mammalian membrane. We identified PepA to be a potential candidate to interact with SHP-1. Inhibition of SHP-1 through PepA to discern IL-10 and IL-12 reciprocity may be assessed in future and furnish us with a potential therapeutic molecule. HSD mice exhibited high pro-inflammatory response to L.major infection which resulted in reduced lesion size. Contrary to observations in HSD mice, infection model exhibited low pro-inflammatory response and increased lesion size with high parasite load. Thus, increase in NFAT5 expression and reduced SHP-1 expression may result in disease resolving effect which can be further studied through incorporation of synthetic circuit using PepA to modulate IL-10 and IL-12 reciprocity.

Streamlined Synthesis of SHP2 Inhibitor GDC-1971 Enhanced by a Telescoped Schotten-Baumann SNAr and Reactive Crystallization Cascade

Streamlined Synthesis of SHP2 Inhibitor GDC-1971 Enhanced by a Telescoped Schotten-Baumann S_<i>N</i>Ar and Reactive Crystallization Cascade

Isotoosendanin exerts anti-tumor effects in NSCLC by enhancing the stability of SHP-2 and inhibiting the JAK/STAT3 pathway

Lung cancer has been considered as a serious problem for the public health system. NSCLC is the main type of lung cancer, and finding improved treatments for NSCLC is a pressing concern. In this study, we have explored the efficacy of isotoosendanin (ITSN) for the treatment of NSCLC, and also explored the potential underlying mechanisms. NSCLC cells were cultured, and colony formation, cell cycle as well as apoptosis assays have been conducted for investigating the biological functions of ITSN on NSCLC cells. Furthermore, target genes of ITSN have been predicted via PharmMapper and SuperPred database, subsequently validated using the drug affinity responsive target stability (DARTS) approach, a cellular thermal shift assay (CETSA) as well as surface plasmon resonance (SPR) analysis. Additionally, ubiquitination experiments have been conducted for the level of ubiquitination of the NSCLC cells. Finally, a nude mouse xenograft model has been established for evaluating the anti-tumor effects of ITSN in vivo. ITSN has shown anti-NSCLC activities both in vitro and in vivo. Mechanistically, ITSN interacts with SHP-2 through enhancing its stability and decreases the level of ubiquitination. Notably, ITSN may regulate the behaviors of NSCLC cells via affecting the JAK/STAT3 signaling, and finally, the anti-tumor effects of ITSN was partially reversed by the application of SHP-2 inhibitor or siRNA of SHP-2. ITSN may exert its anti-tumor effects by directly targeting SHP-2, increasing its stability and minimizing its ubiquitination. These results imply that ITSN could be a revolutionary component for treating NSCLC.

Engineering nanoparticles-enabled tumor-associated macrophages repolarization and phagocytosis restoration for enhanced cancer immunotherapy

Tumor-associated macrophages (TAMs) are pivotal within the immunosuppressive tumor microenvironment (TME), and recently, have attracted intensive attention for cancer treatment. However, concurrently to promote TAMs repolarization and phagocytosis of cancer cells remains challenging. Here, a TAMs-targeted albumin nanoparticles-based delivery system (M@SINPs) was constructed for the co-delivery of photosensitizer IR820 and SHP2 inhibitor SHP099 to potentiate macrophage-mediated cancer immunotherapy. M@SINPs under laser irradiation can generate the intracellular reactive oxygen species (ROS) and facilitate M2-TAMs to an M1 phenotype. Meanwhile, inhibition of SHP2 could block the CD47-SIRPa pathway to restore M1 macrophage phagocytic activity. M@SINPs-mediated TAMs remodeling resulted in the immunostimulatory TME by repolarizing TAMs to an M1 phenotype, restoring its phagocytic function and facilitating intratumoral CTLs infiltration, which significantly inhibited tumor growth. Furthermore, M@SINPs in combination with anti-PD−1 antibody could also improve the treatment outcomes of PD−1 blockade and exert the synergistic anticancer effects. Thus, the macrophage repolarization/phagocytosis restoration combination through M@SINPs holds promise as a strategy to concurrently remodel TAMs in TME for improving the antitumor efficiency of immune checkpoint block and conventional therapy.

Updated safety and efficacy data of combined KRAS G12C inhibitor (glecirasib, JAB-21822) and SHP2 inhibitor (JAB-3312) in patients with KRAS p.G12C mutated solid tumors.

3008 Background: Resistance to KRAS G12C inhibitor in non-small cell lung cancer (NSCLC) can be overcome by SHP2 blockade. This concept was tested in Phase I study of glecirasib combined with JAB-3312 in patients (pts) with KRAS p.G12C mutated tumors. Promising preliminary data of safety and response were reported at the 2023 ESMO (653O). Here, we present the updated safety and efficacy data with treatment response and progression-free survival (PFS) of the combination therapy in front-line NSCLC. Methods: The phase 1/2a study [NCT05288205] evaluated glecirasib plus JAB-3312 in patients with KRAS p.G12C mutated solid tumors. The primary objective of the dose-escalation phase was to assess the safety and tolerability of the combination therapy, and the primary objective of the dose-expansion phase was to assess efficacy. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS by investigator per RECIST1.1 and overall survival. Glecirasib 400 mg or 800 mg daily was combined with various JAB-3312 doses and schedules. Results: As of December 1st, 2023, 179 pts were enrolled, including 157 with NSCLC, 17 with colorectal cancer, and five with other tumor types. Treatment-related adverse events (TRAE) ≥ grade 3 occurred in 41.9% of all pts. There were no treatment-related deaths. Discontinuation of either glecirasib or JAB-3312 due to TRAE occurred in 7.8% of all pts. The AE profile was unchanged from the last ESMO report. The most common ( &gt; 20%) TRAEs included anemia, ALT/AST increased, hypertriglyceridemia, bilirubin increased, neutropenia/leukopenia, creatine kinase increased, and edema. No overlapped toxicity was observed for this combination therapy. Amongst all pts enrolled, 88 had NSCLC and received the combination therapy as front-line treatment in seven dosing groups. The median follow-up duration was 6.1 (range:0.5-16.7) months. Eighty pts had at least once post-treatment efficacy assessment. The ORR was 72.5% (58/80) and DCR was 96.3% (77/80). In the group of glecirasib 800mg QD + JAB-3312 2mg one week on/one week off, the ORR was 77.8% (21/27) and DCR was 92.6% (25/27). The median PFS was not mature by the data cut-off date. The 6-month and 12-month PFS rate were 67.3% and 53.7%, respectively. Additional safety and efficacy data will be presented at the meeting. Conclusions: Glecirasib plus JAB-3312 has a manageable safety profile and a promising ORR and PFS as a front-line treatment for patients with KRAS p.G12C NSCLC. This combination will be further evaluated in a randomized phase III trial in NSCLC. Clinical trial information: NCT05288205 .

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

Integrative analysis discovers Imidurea as dual multitargeted inhibitor of CD69, CD40, SHP2, lysozyme, GATA3, cCBL, and S-cysteinase from SARS-CoV-2 and M. tuberculosis

Two of the deadliest infectious diseases, COVID-19 and tuberculosis (TB), have combined to establish a worldwide pandemic, wreaking havoc on economies and claiming countless lives. The optimised, multitargeted medications may diminish resistance and counter them together. Based on computational expression studies, 183 genes were co-expressed in COVID-19 and TB blood samples. We used the multisampling screening algorithms on the top ten co-expressed genes (CD40, SHP2, Lysozyme, GATA3, cCBL, SIVmac239 Nef, CD69, S-adenosylhomocysteinase, Chemokine Receptor-7, and Membrane Protein). Imidurea is a multitargeted inhibitor for COVID-19 and TB, as confirmed by extensive screening and post-filtering utilising MM\\GBSA algorithms. Imidurea has shown docking and MM\\GBSA scores of −8.21 to −4.75 Kcal/mol and −64.16 to −29.38 Kcal/mol, respectively. The DFT, pharmacokinetics, and interaction patterns suggest that Imidurea may be a drug candidate, and all ten complexes were tested for stability and bond strength using 100 ns for all MD atoms. The modelling findings showed the complex's repurposing potential, with a cumulative deviation and fluctuation of <2 Å and significant intermolecular interaction, which validated the possibilities. Finally, an inhibition test was performed to confirm our in-silico findings on SARS-CoV-2 Delta variant infection, which was suppressed by adding imidurea to Vero E6 cells after infection.

Inhibiting SHP2 reduces glycolysis, promotes microglial M1 polarization, and alleviates secondary inflammation following spinal cord injury in a mouse model.

JOURNAL/nrgr/04.03/01300535-202503000-00030/figure1/v/2024-06-17T092413Z/r/image-tiff Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.