The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models

Tam, Betty; Chiu, Kevin; Chung, Heekyung; Bossard, Carine; Nguyen, John D.; Creger, Emily; Eastman, Brian; Mak, Chi Ching; Ibanez, Maureen; Ghias, Abdullah; Cahiwat, Joseph; Do, Long; Cho, Shawn; Nguyen, Jackie; Deshmukh, V.; Stewart, Josh; Chen, Chiao-Wen; Barroga, Charlene F.; Dellamary, Luis; Kc, Sunil; Phalen, Timothy; Hood, John; Cha, Steven; Yazıcı, Yusuf

doi:10.1016/j.canlet.2019.09.009

Cited by 88 publications

(123 citation statements)

References 42 publications

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“…Via regulation of splicing, CLKs (indirectly) affect a variety of biological processes [ 73 , 74 , 75 ]. For instance, it has been described that CLKs modulate alternative splicing of key Wnt-related genes and consequently the Wnt signaling pathway [ 76 ]. CLKs regulate also the splicing of the TAU protein which plays an essential role in the stabilization of microtubules and thereby impacts processes such as cell division and neuronal activity [ 77 , 78 , 79 ].…”

Section: Biology Of Clksmentioning

confidence: 99%

“…Numerous investigations of the cancer-related biology of CLKs have been supported by the use of small-molecule inhibitors (described in the following chapter) with varying degrees of selectivity. Of those, the inhibitor SM08502 recently entered clinical trials for the treatment of advanced solid tumors [ 76 ], and the compound CX-4945/silmitasertib (which inhibits CLK2 as well as CK2) [ 119 ] for the treatment of cholangiocarcinoma, medulloblastoma, basal cell carcinoma, and multiple myeloma [ 120 ]. CX-4945 could be also applicable in the treatment of glioblastoma where CLK2 modulates phosphorylation of Forkhead box O3a (FOXO3a)/p27 and, consequently, cell cycle and survival of tumor cells [ 121 ].…”

Section: Clks As Therapeutic Targetsmentioning

confidence: 99%

“…Table 2 contains the published values obtained in primary biochemical assays; however, for their direct comparison it is important to keep in mind that these data were often obtained from various sources/assays or from the same (similar) assay but under unequal conditions (e.g., using different concentrations of ATP). On the other hand, some studies report a direct comparison of several (usually two or three) inhibitors from different classes/publications, profiling them in the same assay [ 76 , 133 , 134 , 135 , 136 ].…”

Section: Small-molecule Clk Inhibitorsmentioning

confidence: 99%

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Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

Moyano

Němec

Paruch

2020

IJMS

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Protein kinases represent a very pharmacologically attractive class of targets; however, some members of the family still remain rather unexplored. The biology and therapeutic potential of cdc-like kinases (CLKs) have been explored mainly over the last decade and the first CLK inhibitor, compound SM08502, entered clinical trials only recently. This review summarizes the biological roles and therapeutic potential of CLKs and their heretofore published small-molecule inhibitors, with a focus on the compounds’ potential to be utilized as quality chemical biology probes.

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Section: Biology Of Clksmentioning

confidence: 99%

Section: Clks As Therapeutic Targetsmentioning

confidence: 99%

Section: Small-molecule Clk Inhibitorsmentioning

confidence: 99%

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Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

Moyano

Němec

Paruch

2020

IJMS

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“…In the cell nucleus, CLKs phosphorylate serine/arginine-rich proteins, release them into the nucleoplasm and then regulate AS of genes. Small molecule inhibitors against these CLKs were developed and exhibited growth suppression, apoptosis induction and antitumor effect [40,41]. Here, we found that CLK1 itself can be alternatively spliced.…”

Section: Discussionmentioning

confidence: 94%

Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Lian

Wang

Shen

et al. 2020

Preprint

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Background: Alternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression. Understanding the most common AS events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC.Methods: Publicly available RNA-seq data of 28 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify AS events using PSI and DEXSeq methods. Result: The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified AS events in 9 genes in CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6). Except for CHEK1, all other 8 splicing events were confirmed by TCGA data with 382 CRC tumors and 51 normal controls. The combination of three splicing events was used to build a logistic regression model that can predict sample type (CRC or normal) with near perfect performance (AUC=1). Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The AS features of the 9 genes are highly consistent with previous reports and/or relevant to cancer biology. Conclusions: The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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“…One isoform of CD44 has been shown to activate RAS through the phosphorylation of Erk [54]. In addition, the small molecule, SM08502, reduced the phosphorylation of splicing factors and generated isoforms of Wnt pathway genes which inhibited gastrointestinal tumors [55]. The reports about alternative splicing and protein glycosylation is limited.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel alternative splicing events associated with tumorigenesis, protein modification, and immune microenvironment in early-onset gastric cancer

Zhang

Zhu

2020

Preprint

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BackgroundAlternative splicing (AS), e.g. tandem alternative polyadenylation (TAPA), has emerged as major post-transcriptional modification events in human disease. However, the roles of AS and TAPA in early-onset gastric cancer (EOGC) have not been revealed.MethodsThe global AS profiles of 80 EOGC patient samples from the European Nucleotide Archive (PRJNA508414) were analyzed. The EOGC-specific AS events (ESASs) were identified in both EOGC and adjacent non-tumor tissues. Functional enrichment analysis, Splicing network, Alternative Polyadenylation (APA) core factor network, and cell abundancy analysis were performed. Furthermore, the landscapes of AS events in the varied subtypes of EOGC patients, including various protein modifications and viral infections, were evaluated.ResultsOverall, 66,075 AS events and 267 ESASs were identified in EOGC. In these events, 4809 genes and 6152 gene isoforms were found to be aberrantly expressed in EOGC. The Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses showed that significant pathway alterations might exist in these AS events, genes, and gene isoforms. Moreover, the Protein-protein interaction (PPI) network analysis revealed that UBC, NEK2, EPHB2, and DCTN1 genes were the hub genes in the AS events in EOGC. The immune cell infiltration analysis indicated a correlation between the AS events and the cancer immune microenvironment. The distribution of AS events in varied EOGC subtypes was uneven. The numbers of AS events related to protein phosphorylation and glycosylation were 82 and 85, respectively, which suggested a high association between AS events and protein modification in EOGC.ConclusionThe study highlighted the vital roles of AS in EOGC, including modulating the specific protein modification and reshaping the cancer immune microenvironment, and yielded new insights into the diagnosis of EOGC as well as cancer treatment.

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The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models

Cited by 88 publications

References 42 publications

Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Identification of novel alternative splicing events associated with tumorigenesis, protein modification, and immune microenvironment in early-onset gastric cancer

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