Last update 01 Nov 2024

SRPK1 x SRPK2

Last update 01 Nov 2024

Basic Info

Related Targets

SRPK1SRPK2

Drugs associated with SRPK1 x SRPK2

SRPKIN-1

Target

SRPK1 x SRPK2

Mechanism

SRPK1 antagonists [+1]

Active Org.

Dana-Farber Cancer Institute, Inc.

Originator Org.

Dana-Farber Cancer Institute, Inc.

Active Indication

Age Related Macular Degeneration

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SRPK1 x SRPK2

100 Translational Medicine associated with SRPK1 x SRPK2

0 Patents (Medical) associated with SRPK1 x SRPK2

Literatures (Medical) associated with SRPK1 x SRPK2

01 Sep 2022·Biochemical Pharmacology

The SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (SRPIN340) increases the immune response against metastatic melanoma in mice

Article

Author: de Paiva, Janine Cerqueira ; de Andrade Barros, Marcus Vinícius ; Caetano, Mônica Maria Magalhães ; Almeida, Alisson Andrade ; de Oliveira, Leandro Licursi ; do Vale, Juliana Alves ; de Souza, Ana Paula Martins ; Gonçalves, Victor Hugo Sousa ; Guimarães, Gabriela Rapozo ; Boroni, Mariana ; Machado-Neves, Mariana ; Moreira, Gabriela Alves ; Martim, Fernanda Rebellato Giordano ; Silva, Lucas Viana Gomes ; Fietto, Juliana Lopes Rangel ; Bressan, Gustavo Costa ; de Oliveira Santos, Leandro ; Silva-Júnior, Abelardo ; Teixeira, Róbson Ricardo

Cancers have a strong relationship with immune cells in their microenvironment, which significantly influences tumor proliferation and progression. Thus, pharmacological strategies that stimulate the immune system to combat tumor cells are promising for better therapeutic efficacy. Deregulated expression of the splicing regulatory serine arginine protein kinases (mostly SRPK1 and SRPK2) has been found in different cancer types, leading to the expression of isoforms related to tumor growth and metastasis. The microenvironment of melanoma exhibits a strong presence of immune cells, which significantly influences tumor progression, and around 50% of cutaneous melanoma patients benefit from targeted immunotherapy. Here, we analyzed human malignant melanoma single-cell gene expression data and observed that SRPK1/2 overexpression correlates with immune system pathway alterations. In further analysis, we observed an increased presence of immune cells in biopsies from mice bearing metastatic melanoma treated with SRPIN340, a well-known SRPK1/2 pharmacological inhibitor. Local treatments increased the expression of proinflammatory cytokines at the tumor lesions and the activity of the spleen, accompanied by reduced pulmonary metastasis foci, edema formation, and alveolar congestion. In in vitro assays, SRPIN340 also potentiated immunological susceptibility, by increasing the expression of the antigen presenting MHCI and MHCII molecules and by increasing the ability of B16F10 cells to attract splenic cells in transwell assays. Taken together, these results reveal that the antimetastatic effect of SRPIN340 can also involve an increased immune response, which suggests additional functional clues for SRPKs in tumor biology.

01 Jun 2020·Toxicology in Vitro

Combined SRPK and AKT pharmacological inhibition is synergistic in T-cell acute lymphoblastic leukemia cells

Article

Author: Teixeira, Róbson Ricardo ; de Souza, Luciana Ângelo ; Siqueira, Raoni Pais ; Caetano, Mônica Maria Magalhães ; Barros, Marcus Vinícius de Andrade ; Bressan, Gustavo Costa ; Simaroli, Natália Borges ; Teixeira, Felipe Roberti ; Dos Passos, Patrícia Maria Siqueira ; Fietto, Juliana Lopes Rangel ; de Souza, Ana Paula Martins ; Silva-Júnior, Abelardo ; de Oliveira, Leandro Licursi

The serine/arginine protein kinases respond to the EGFR-PI3K-AKT signaling module in the context of pre-mRNA alternative splicing regulation. These enzymes (notably SRPK1 and SRPK2) have been found dysregulated in a variety of cancers, which suggests them as promising drug targets in oncology. SRPK2 has been related to leukemia cells proliferation and found preferentially overexpressed in T-cell acute lymphoblastic leukemia (T-ALL). Previously, synergistic combination between vincristine and SRPK inhibitors has been observed in leukemia cells in vitro. Herein we sought to evaluate the in vitro combinatory effects of inhibiting SRPK and multiple other kinase targets from the EGFR pathway in T-ALL, a hematological malignancy with a still poor prognosis. We found that the combined SRPK and AKT pharmacological inhibition is synergistic in Jurkat, CCRF-CEM, and TALL-1 (all T-ALL) but not in HL60, an acute myelogenous leukemia cell lineage. Combined treatments also impaired SR proteins phosphorylation in accordance with an improved suppression of SRPK activity. Furthermore, the synergism of treatments seemed associated with apoptosis triggering, as revealed by flow cytometry analyses. Taken together, these results suggest the therapeutic potential of the combined SRPK and AKT pharmacological inhibition against T-ALL.

01 Apr 2020·Cancer Reports

CRISPR/Cas9‐mediated double knockout of SRPK1 and SRPK2 in a nasopharyngeal carcinoma cell line

Article

Author: Prattapong, Pongphol ; Janvilisri, Tavan ; Ngernsombat, Chawalit ; Aimjongjun, Sathid

AbstractBackgroundSerine‐arginine protein kinase (SRPK) is a regulator of alternative splicing events via phosphorylation of splicing factor proteins. Oncogenic roles of SRPK1 and SRPK2 have been reported in various types of cancer. To date, only SRPK1/2 specific inhibitors and small interfering RNA (siRNA) have been used for halting their function momentarily; however, there is no attempt to generate SRPK1/2 stable knockout cancer cells as a tool to investigate their roles in tumorigenesis.AimOur objective is therefore to establish a nasopharyngeal carcinoma (NPC) cell line with stable SRPK1 or SRPK2 knockout and SRPK1/2 double knockout as a model to investigate their potential roles in NPC.Methods and ResultsCNE1 was selected as a representative of NPC cell lines to create single and double knockout of SRPK1/2 proteins. SRPK1/2 KO plasmid with cas9, green fluorescent protein (GFP), and gRNA expression was cotransfected with SRPK1/2 homology‐directed repair (HDR) plasmid containing puromycin resistance, red fluorescent protein (RFP), and 5′ and 3′ arm sequence for homologous recombination to CNE1 cells. The transfected CNE1 cells with GFP and RFP expression were sorted through fluorescence‐activated cell sorting for further treatment with puromycin containing medium. This step generated stable single knockout of SRPK1 and SRPK2. The SRPK2 knockout NPC cells were used as a precursor for double knockout generation via transfection with Cre plasmid for excision of inserted material to generate puromycin‐sensitive SRPK2 knockout clone. The puromycin‐sensitive SRPK2 knockout cells were transfected with SRPK1 KO/HDR plasmid and treated with puromycin‐containing medium. The puromycin‐resistant cells of SRPK1/2 stable double knockout were expanded, and the corresponding protein expression was confirmed by western immunoblotting analysis.ConclusionSingle and double knockout of SRPK1/2 were established using clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR‐associated 9 (Cas9) system in an NPC cell line as a model for investigation of their splicing mechanism in NPC.

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