Immunomodulatory activity of trifluoromethyl arylamides derived from the SRPK inhibitor SRPIN340 and their potential use as vaccine adjuvant

Mendes, Flávia Carneiro; Paiva, Janine Cerqueira de; Silva, Elói Quintas Gonçalves da; Santos, Marcelo Rocha dos; Lima, Graziela Domingues de Almeida; Moreira, Guilherme Musse; Silva, Lucas Viana Gomes; Agripino, Joice de Melo; Souza, Ana Paula Martins de; Mendes, Tiago; Machado‐Neves, Mariana; Teixeira, Róbson Ricardo; Silva-Júnior, Abelardo; Fietto, Juliana Lopes Rangel; Oliveira, Leandro Licursi de; Bressan, Gustavo Costa

doi:10.1016/j.lfs.2022.120849

Cited by 3 publications

(1 citation statement)

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“…SRPIN340 was the first discovered SRPK inhibitor with antiviral potential (Fukuhara et al, 2006). In the tumor context, we have demonstrated that SRPK1/2 pharmacological inhibition by the classical inhibitor SRPIN340 and other derivatives decreased the invasive capacity of metastatic melanoma B16F10 cells in vitro and reduced the formation of pulmonary nodules in vivo, which can be related to immune system activation (Moreira et al, 2018;Mendes et al, 2022;Moreira et al, 2022). However, as SRPIN340 inhibits SRPK1 and to a lesser extent SRPK2, as well other splicing kinases (Fukuhara et al, 2006), these data are limited in informing which SRPK1/ 2 member is relevant for melanoma progression.…”

Section: Introductionmentioning

confidence: 96%

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

et al. 2022

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Melanoma is one of the most aggressive tumors, and its lethality is associated with the ability of malignant cells to migrate and invade surrounding tissues to colonize distant organs and to generate widespread metastasis. The serine/arginine protein kinases 1 and 2 (SRPK1 and SRPK2) are classically related to the control of pre-mRNA splicing through SR protein phosphorylation and have been found overexpressed in many types of cancer, including melanoma. Previously, we have demonstrated that the pharmacological inhibition of SRPKs impairs pulmonary colonization of metastatic melanoma in mice. As the used compounds could target at least both SRPK1 and SRPK2, here we sought to obtain additional clues regarding the involvement of these paralogs in melanoma progression. We analyzed single-cell RNA sequencing data of melanoma patient cohorts and found that SRPK2 expression in melanoma cells is associated with poor prognosis. Consistently, CRISPR-Cas9 genome targeting of SRPK2, but not SRPK1, impaired actin polymerization dynamics as well as the proliferative and invasive capacity of B16F10 cells in vitro. In further in vivo experiments, genetic targeting of SRPK2, but not SRPK1, reduced tumor progression in both subcutaneous and caudal vein melanoma induction models. Taken together, these findings suggest different functional roles for SRPK1/2 in metastatic melanoma and highlight the relevance of pursuing selective pharmacological inhibitors of SRPK2.

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Section: Introductionmentioning

confidence: 96%

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

et al. 2022

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Effects of 1H-1,2,3-Triazole Derivatives of 3-O-Acetyl-11-Keto-Beta-Boswellic Acid from Boswellia sacra Resin on T-Cell Proliferation and Activation

Meyiah,

Avula,

Al-Harrasi

et al. 2024

Pharmaceuticals

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Background: 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA), a triterpene natural product, is one of the main natural products of Boswellia sacra resin (BSR) and has reported biological and immunomodulatory effects. 1H-1,2,3-triazole derivatives of β-AKBA (named 6a–6d) were synthesized from β-AKBA. The 1H-1,2,3-triazole compounds are also known to have a wide range of biological and pharmacological properties as demonstrated by in vitro and in vivo studies. This study aimed to investigate the effects of these 1H-1,2,3-triazole derivatives of β-AKBA on human T-cell proliferation and activation. Methods: PBMCs isolated from healthy donors were activated by anti-CD3/CD28 monoclonal antibodies in the presence of β-AKBA (1) or 1H-1,2,3-triazole derivatives of β-AKBA or DMSO controls. Results: We found that similar to the parent compound β-AKBA (1), derivatives 6a, 6b, and 6d significantly inhibited T-cell expansion/proliferation and reduced the levels of CD25 activation marker on CD4+ and CD8+ T cells without exerting significant cytotoxic effects on T-cell viability at a concentration of 25 µM. However, compound 6c further inhibited T-cell expansion/proliferation and CD25 expression, but had a significant cytotoxic effect on cell viability at similar concentrations of 25 µM. Conclusions: These findings demonstrate the immunoinhibitory effects of β-AKBA (1) and its corresponding triazole derivatives on T-cell proliferation and activation, highlighting the promising therapeutic potential of these compounds in T-cell-mediated diseases.

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Novel Diamides Inspired By Protein Kinase Inhibitors As Anti- Trypanosoma Cruzi Agents: In Vitro and In Vivo Evaluations

Vieira da Silva Torchelsen,

Fernandes Pedrosa,

Rodrigues

et al. 2023

Future Med. Chem.

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Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi. The involvement of serine-arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC50/IC50 in two in vitro models. The most active compound, 3j, was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results: 3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruzi in vitro and in vivo.

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Immunomodulatory activity of trifluoromethyl arylamides derived from the SRPK inhibitor SRPIN340 and their potential use as vaccine adjuvant

Cited by 3 publications

References 61 publications

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

Effects of 1H-1,2,3-Triazole Derivatives of 3-O-Acetyl-11-Keto-Beta-Boswellic Acid from Boswellia sacra Resin on T-Cell Proliferation and Activation

Novel Diamides Inspired By Protein Kinase Inhibitors As Anti- Trypanosoma Cruzi Agents: In Vitro and In Vivo Evaluations

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