Discovery of Pyridazinone and Pyrazolo[1,5-<i>a</i>]pyridine Inhibitors of C-Terminal Src Kinase

O’Malley, Daniel P.; Ahuja, Vijay T.; Fink, Brian E.; Cao, Carolyn; Wang, Cindy; Swanson, Jesse; Wee, Susan; Gavai, Ashvinikumar V.; Tokarski, John S.; Critton, D.A.; Paiva, Anthony; Johnson, Benjamin M.; Szapiel, Nicolas; Xie, Dan

doi:10.1021/acsmedchemlett.9b00354

Cited by 21 publications

(10 citation statements)

References 16 publications

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“…Pyrazolo[1,5- a ]pyridines are prevalent in a wide array of biologically active compounds and marketed drug molecules . Given the salient biological profiles of pyrazolo[1,5- a ]pyridine-based molecules, it is no surprise that a handful of powerful approaches have been developed to construct this skeleton .…”

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confidence: 99%

Regioselective Synthesis of Pyrazolo[1,5-a]pyridine via TEMPO-Mediated [3 + 2] Annulation–Aromatization ofN-Aminopyridines and α,β-Unsaturated Compounds

et al. 2022

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A TEMPO-mediated [3 + 2] annulation–aromatization protocol for the preparation of pyrazolo[1,5-a]pyridines from N-aminopyridines and α,β-unsaturated compounds was developed. The procedure offered multisubstituted pyrazolo[1,5-a]pyridines in good to excellent yield with high and predictable regioselectivity. The modification of marketed drugs including Loratadine, Abiraterone, and Metochalcone, and a one-pot three-step gram scale synthesis of key intermediate for the preparation of Selpercatinib were demonstrated. Mechanism studies show that TEMPO serves both as a Lewis acid and as an oxidant.

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confidence: 99%

Regioselective Synthesis of Pyrazolo[1,5-a]pyridine via TEMPO-Mediated [3 + 2] Annulation–Aromatization ofN-Aminopyridines and α,β-Unsaturated Compounds

et al. 2022

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“…CSK is a no-receptor tyrosine kinase that is considered to be an indispensable negative regulator of Src family kinases (SFKs) [29]. It consists of three Src homologous domains: N-terminal Src homologous 3 (SH3), SH2, and C-terminal kinase [30]. Extensive evidence has shown that CSK plays an important role in the signal transduction pathways of immune receptors, including promoting the innate immune response and inhibiting T cell or mast cell activation [31,32].…”

Section: Discussionmentioning

confidence: 99%

Immune-Related Genes: Potential Prognostic Factors and Regulatory Targets for Cervical Carcinoma

Xie

Liu

et al. 2021

Journal of Nanomaterials

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Background. Advanced cervical carcinoma carries a particularly poor prognosis, and few treatment options exist. It is very important to find a method to evaluate the prognosis and survival rate of cervical carcinoma. The metastasis and invasion of cervical carcinoma are closely related to tumor immune microenvironment (TIME), and immune related genes (IRGs) are involved in the regulation of TIME. However, the role of IRGs in the prognosis of patients with cervical carcinoma remains unclear. Methods. The gene expression profiles of cervical carcinoma were downloaded from The Cancer Genome Atlas (TCGA) database, and IRG information were obtained from the ImmPort database. The IRGs were screened by coexpression analysis and were also performed function enrichment and pathway analyses. A prognosis model was built based on IRGs, and the risk score (RS) was calculated by Cox regression analysis. The accuracy was assessed by receiver operating characteristic (ROC) curve analysis. Besides, the relationship between RS and TIMER-generating immune cell content was performed by immune infiltration analysis. Results. In a total of 2503 differentially expressed genes (DEGs), 204 genes were IRGs, 20 of which were crucially correlated with the survival rate of cervical carcinoma. On the basis of Cox regression analysis, 6 IRGs were included in the prognosis model to calculate the RS. Kaplan-Meier survival and ROC analyses showed that the prognostic function of the model was superior to the current model constructed by clinicopathological risk factors. In addition, these 6 IRG signatures were related to the immune infiltration levels of six immune cells and the overall survival (OS) of cervical carcinoma. Finally, C-terminal Src kinase (CSK) gene is related to tumor metastasis, and Slit guidance ligand 2 (Slit2) is related to tumor clinical stage. Conclusion. The IRGs may contribute to the stratification of prognosis, and CSK/Slit2 may be two suppressor genes for cervical carcinoma.

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“…Antibodies: anti-PEAK2 and anti-PEAK2 pY413 were described in [ 11 ]; anti-ABL was described in [ 27 ]; anti-ABL pY412, anti-ERK1/2, anti-ERK1/2 pT202/Y204, anti-AKT, anti-AKT pS473, anti-pTyr clone pY1000 Sepharose bead conjugated (PTM Scan, Cell Signalling Technology, Danvers, MA, USA); anti-Hes1, anti-Actin, anti-AMPK, and anti-AMPK pT172; anti-Myc tag (9B11) were from Cell Signalling Technology; antitubulin (gift from N. Morin, CRBM, Montpellier, France); anti-ATOH1 (EPR6419, Abcam, Cambridge, UK); anti-pY418 SRC (Biosource, Camarillo, California, US), anti-pTyr 4G10 (gift from P. Mangeat, CRBM, Montpellier, France); anti-cst1 (that recognizes SRC, FYN and YES) was described in [ 28 ]; antirabbit IgG-HRP and antimouse IgG-HRP (GE Healthcare, Chicago, IL, USA). Kinase inhibitors: Imatinib, dasatinib, bosutinib, lapatinib, PP2 were from Sigma-Aldrich, (St. Louis, MI, USA); nilotinib and CSKi (compound 13 ) [ 29 ] was a gift from Novartis (Basel, Switzerland) and Bristol-Myers Squibb Company (New York, NY, USA), respectively. Fibronectin human plasma (F0895) and rat tail collagen I (#C3867) were from Sigma.…”

Section: Materiel and Methodsmentioning

confidence: 99%

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

Lecointre

Fourgous

Montarras

et al. 2022

Cancers

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The PEAK family pseudokinases are essential components of tyrosine kinase (TK) pathways that regulate cell growth and adhesion; however, their role in human cancer remains unclear. Here, we report an oncogenic activity of the pseudokinase PEAK2 in colorectal cancer (CRC). Notably, high PRAG1 expression, which encodes PEAK2, was associated with a bad prognosis in CRC patients. Functionally, PEAK2 depletion reduced CRC cell growth and invasion in vitro, while its overexpression increased these transforming effects. PEAK2 depletion also reduced CRC development in nude mice. Mechanistically, PEAK2 expression induced cellular protein tyrosine phosphorylation, despite its catalytic inactivity. Phosphoproteomic analysis identified regulators of cell adhesion and F-actin dynamics as PEAK2 targets. Additionally, PEAK2 was identified as a novel ABL TK activator. In line with this, PEAK2 expression localized at focal adhesions of CRC cells and induced ABL-dependent formation of actin-rich plasma membrane protrusions filopodia that function to drive cell invasion. Interestingly, all these PEAK2 transforming activities were regulated by its main phosphorylation site, Tyr413, which implicates the SRC oncogene. Thus, our results uncover a protumoural function of PEAK2 in CRC and suggest that its deregulation affects adhesive properties of CRC cells to enable cancer progression.

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Discovery of Pyridazinone and Pyrazolo[1,5-a]pyridine Inhibitors of C-Terminal Src Kinase

Cited by 21 publications

References 16 publications

Regioselective Synthesis of Pyrazolo[1,5-a]pyridine via TEMPO-Mediated [3 + 2] Annulation–Aromatization ofN-Aminopyridines and α,β-Unsaturated Compounds

Regioselective Synthesis of Pyrazolo[1,5-a]pyridine via TEMPO-Mediated [3 + 2] Annulation–Aromatization ofN-Aminopyridines and α,β-Unsaturated Compounds

Immune-Related Genes: Potential Prognostic Factors and Regulatory Targets for Cervical Carcinoma

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer

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