Development of 2′-aminospiro [pyrano[3,2–c]quinoline]-3′-carbonitrile derivatives as non-ATP competitive Src kinase inhibitors that suppress breast cancer cell migration and proliferation

Ramadan, Mohamed; Elshaier, Yaseen A.M.M.; Aly, Ashraf A.; Abdel‐Aziz, Mohamed; Fathy, Hazem M.; Brown, Alan B.; Pridgen, Jacey R.; Dalby, Kevin N.; Kaoud, Tamer S.

doi:10.1016/j.bioorg.2021.105344

Cited by 20 publications

(9 citation statements)

References 46 publications

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“…Src is highly overexpressed and activated in different epithelial cancers, especially breast cancer. It is well-documented to promote cancer cell plasticity, motility and invasion, and has been described as a key player in EMT [ 47 , 48 ]. Tyr23 Phosphorylation of ANXA2 by Src tyrosine kinase promotes proliferation, migration, and invasion of tumor cells [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

Long

Chong

Lyu

et al. 2022

J Exp Clin Cancer Res

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Background Early metastasis is a key factor contributing to poor breast cancer (BC) prognosis. Circulating tumor cells (CTCs) are regarded as the precursor cells of metastasis, which are ultimately responsible for the main cause of death in BC. However, to date molecular mechanisms underlying CTC formation in BC have been insufficiently defined. Methods RNA-seq was carried out in primary tissues from early-stage BC patients (with CTCs≥5 and CTCs = 0, respectively) and the validation study was conducted in untreated 80 BC patients. Multiple in vitro and in vivo models were used in functional studies. Luciferase reporter, ChIP-seq, CUT&Tag-seq, and GST-pulldown, etc. were utilized in mechanistic studies. CTCs were counted by the CanPatrol™ CTC classification system or LiquidBiospy™ microfluidic chips. ERK1/2 inhibitor SCH772984 was applied to in vivo treatment. Results Highly expressed FOXD1 of primary BC tissues was observed to be significantly associated with increased CTCs in BC patients, particularly in early BC patients. Overexpressing FOXD1 enhanced the migration capability of BC cells, CTC formation and BC metastasis, via facilitating epithelial-mesenchymal transition of tumor cells. Mechanistically, FOXD1 was discovered to induce RalA expression by directly bound to RalA promotor. Then, RalA formed a complex with ANXA2 and Src, promoting the interaction between ANXA2 and Src, thus increasing the phosphorylation (Tyr23) of ANXA2. Inhibiting RalA-GTP form attenuated the interaction between ANXA2 and Src. This cascade culminated in the activation of ERK1/2 signal that enhanced metastatic ability of BC cells. In addition, in vivo treatment with SCH772984, a specific inhibitor of ERK1/2, was used to dramatically inhibit the CTC formation and BC metastasis. Conclusion Here, we report a FOXD1-dependent RalA-ANXA2-Src complex that promotes CTC formation via activating ERK1/2 signal in BC. FOXD1 may serve as a prognostic factor in evaluation of BC metastasis risks. This signaling cascade is druggable and effective for overcoming CTC formation from the early stages of BC.

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Section: Discussionmentioning

confidence: 99%

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

Long

Chong

Lyu

et al. 2022

J Exp Clin Cancer Res

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“…The carbonyl group showed hydrogen bond interaction with Ser348 in the ATP binding site. [33] Aqlan synthesized coumarin clubbed pyrazole hybrids and the researcher predicted the tyrosine kinase target and then performed molecular docking and ADMET studies to validate the predicted target against Src kinase enzyme and find out the affinity towards the kinase enzyme. The docking study revealed that compounds 19, 20 and 21 (Figure 12) showed excellent binding free energy ranging from À 15.55 to À 17.92 kcal/mol that explained the synthesized derivatives attached very well in the binding pocket of Src kinase.…”

Section: Recent Development Of Src Kinase Inhibitorsmentioning

confidence: 99%

“…In the breast cancer cell lines MDA‐MB‐231 and MCF7, 1.6 μM of 18 were adequate to reduce Src, Fak, and paxillin phosphorylation. The carbonyl group showed hydrogen bond interaction with Ser348 in the ATP binding site [33] …”

Section: Recent Development Of Src Kinase Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure‐Activity Relationship

Teli¹,

Pal²,

Maji³

et al. 2023

Chemistry & Biodiversity

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The physiological Src proto‐oncogene is a protein tyrosine kinase receptor that served as the essential signalling pathway in different types of cancer. The etiology of cancer involved various signalling pathways and Src signalling pathways are also involved in those clusters. Although the dysregulation of Src kinase resulted in cancer being discovered in the late 19th century it is still considered a cult pathway because it is not much explored by different medicinal chemists and oncologists. In this review, we have elaborated about the structure and activation of Src kinase, as well as the development of Src kinase inhibitors. Our group also provided a comprehensive overview of Src inhibitors throughout the last two decades, including their biological activity, structure‐activity relationship, and Src kinase selectivity. The Src binding pocket has been investigated in detail to better comprehend the interaction of Src inhibitors with amino acid residues. We have strengthened the literature with our contribution in terms of molecular docking and ADMET studies of top compounds. We hope that the current analysis will be a useful resource for researchers and provide glimpse of direction toward the design and development of more specific, selective, and potent Src kinase inhibitors.

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“…The reaction yields were not significantly affected by increasing the amount of L-proline. For 10-14 h, 2-(2,7-dibromo-9H-fluoren-9-ylidene) malononitrile as well as 4-hydroxy quinoline analogues, a-f were refluxed in dried pyridine to yield 2 0 -amino-2,7-dibromo-5 0 ,6 0 -dihydrospiro (fluorene 9,4 0 -pyrano [3,2-c] quinoline)-3 0carbonitrile analogues 21a-f with yields of 77%-83% (Scheme 13) [71]. Analogues 21b, 21c, and 21d all had IC50 values of 4.9, 5.9, and 0.9 μM, respectively, for inhibition of Src kinase activity.…”

Section: C 34fmentioning

confidence: 99%

“…Analogues 21b , 21c , and 21d all had IC50 values of 4.9, 5.9, and 0.9 μM, respectively, for inhibition of Src kinase activity. In HEK293 cells, however, they had no effect on the MDM2/p53 interaction, which has been implicated in some spirocyclic compounds' toxic effects [71].…”

Section: Synthesis Strategies For Pyranoquinolone Derivatives and The...mentioning

confidence: 99%

Pyranoquinolone derivatives: A potent multi‐targeted pharmacological scaffold

Uppal

Mir

Chawla

et al. 2022

Journal of Heterocyclic Chem

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The search for new heterocyclic compounds with potential bioactivities continues despite the fact that extensive work has already been done on pyranoquinolones. Researchers throughout the world have used the pyranoquinolone nucleus extensively to generate a wide variety of bioactive heterocycles that target a wide spectrum of biological targets. An in-depth investigation into possible pyranoquinolone derivatives and their pharmacological importance is the focus of this overview of synthetic techniques. Researchers and medicinal chemists can benefit from this review by developing new pyranoquinolone nucleus leads that are very effective and have fewer adverse effects than existing ones.

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Development of 2′-aminospiro [pyrano[3,2–c]quinoline]-3′-carbonitrile derivatives as non-ATP competitive Src kinase inhibitors that suppress breast cancer cell migration and proliferation

Cited by 20 publications

References 46 publications

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

FOXD1-dependent RalA-ANXA2-Src complex promotes CTC formation in breast cancer

Medicinal Chemistry Perspectives on Recent Advances in Src Kinase Inhibitors as a Potential Target for the Development of Anticancer Agents: Biological Profile, Selectivity, Structure‐Activity Relationship

Pyranoquinolone derivatives: A potent multi‐targeted pharmacological scaffold

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