Discovery of Novel DUSP4 Inhibitors through the Virtual Screening with Docking Simulations

Park, Hwangseo; Jeon, Tae Jin; Chien, Pham Ngoc; Park, So Ya; Oh, Sung Min; Kim, Seung Jun; Ryu, Seong Eon

doi:10.5012/bkcs.2014.35.9.2655

Cited by 7 publications

(4 citation statements)

References 23 publications

(11 reference statements)

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“…All these data together point at DUSP4, enzyme regulated by COX-2, as a factor whose overexpression leads to CRC development and invasion, and which can be a promising therapeutic target. Moreover, DUSP4 specific inhibitors have been described (Park et al, 2014) supporting its clinical testing in CRC at least in some drug resistant tumors.…”

Section: Dual-specificity Mapk Phosphatasementioning

confidence: 92%

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is one of the most common and recurrent types of cancer, with high mortality rates. Several clinical trials and meta-analyses have determined that the use of pharmacological inhibitors of cyclooxygenase 2 (COX-2), the enzyme that catalyses the rate-limiting step in the synthesis of prostaglandins (PG) from arachidonic acid, can reduce the incidence of CRC as well as the risk of recurrence of this disease, when used together with commonly used chemotherapeutic agents. These observations suggest that inhibition of COX-2 may be useful in the treatment of CRC, although the current drugs targeting COX-2 are not widely used since they increase the risk of health complications. To overcome this difficulty, a possibility is to identify genes regulated by COX-2 activity that could give an advantage to the cells to form tumors and/or metastasize. The modulation of those genes as effectors of COX-2 may cancel the beneficial effects of COX-2 in tumor transformation and metastasis. A review of the available databases and literature and our own data have identified some interesting molecules induced by prostaglandins or COX-2 that have been also described to play a role in colon cancer, being thus potential pharmacological targets in colon cancer. Among those mPGES-1, DUSP4, and 10, Programmed cell death 4, Trop2, and many from the TGFb and p53 pathways have been identified as genes upregulated in response to COX-2 overexpression or PGs in colon carcinoma lines and overexpressed in colon tumor tissue. Here, we review the available evidence of the potential roles of those molecules in colon cancer in the context of PG/ COX signaling pathways that could be critical mediators of some of the tumor growth and metastasis advantage induced by COX-2. At the end, this may allow defining new therapeutic targets/drugs against CRC that could act specifically against tumor cells and would be effective in the prevention and treatment of CRC, lacking the unwanted side effects of COX-2 pharmacological inhibitors, providing alternative approaches in colon cancer.

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Section: Dual-specificity Mapk Phosphatasementioning

confidence: 92%

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

et al. 2020

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“…Park et al ( 72 ) sought to identify small-molecule inhibitors of MKP2 using a structure-based virtual screen with docking simulation and in vitro enzymatic assays. Using the existing crystal structure of the catalytic domain of MKP2 ( 54 ), they performed a virtual screen using a docking library of 260,000 natural and synthetic compounds.…”

Section: The Mkp Inhibitor Challengementioning

confidence: 99%

“…The catalytic domain of MKP2 was used for enzymatic assays with these compounds using the substrate 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP). Five compounds, labeled as Compounds 1–5, inhibited MKP2 by more than 50% at a 10-μM dose with IC 50 values of 3.5, 6.9, 9.7, 10.2, and 10.8 μM, respectively ( 72 ). MKP7, which is highly homologous to MKP2, was also screened, and Compounds 1–3 demonstrated similar efficacies for both phosphatases, while Compounds 4–5 preferentially inhibited MKP2 ( Figure 3 ).…”

Section: The Mkp Inhibitor Challengementioning

confidence: 99%

“…At the time of the study, the crystal structure of MKP7 had yet to be solved, and so the computational three-dimensional structure used the highly homologous crystal structure of MKP4 as a template ( 46 ). The same 260,000-compound library from the MKP2 screen ( 72 ) was used, and 148 commercially available compounds were tested in an in vitro assay against the purified PTP domain of MKP7. Seven top hits, labeled Compounds 1–7, were identified that inhibited MKP7 by more than 50% at a concentration of 20 μM, with IC 50 values ranging from 1.3 to 21.3 μM ( 98 ).…”

Section: The Mkp Inhibitor Challengementioning

confidence: 99%

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Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?

Shillingford

Bennett

2023

Annu. Rev. Pharmacol. Toxicol.

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Phosphatases and kinases maintain an equilibrium of dephosphorylated and phosphorylated proteins, respectively, that are required for critical cellular functions. Imbalance in this equilibrium or irregularity in their function causes unfavorable cellular effects that have been implicated in the development of numerous diseases. Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of protein substrates on tyrosine residues, and their involvement in cell signaling and diseases such as cancer and inflammatory and metabolic diseases has made them attractive therapeutic targets. However, PTPs have proved challenging in therapeutics development, garnering them the unfavorable reputation of being undruggable. Nonetheless, great strides have been made toward the inhibition of PTPs over the past decade. Here, we discuss the advancement in small-molecule inhibition for the PTP subfamily known as the mitogen-activated protein kinase (MAPK) phosphatases (MKPs). We review strategies and inhibitor discovery tools that have proven successful for small-molecule inhibition of the MKPs and discuss what the future of MKP inhibition potentially might yield.

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Implementation of docking, molecular dynamics and free energy to investigate drug potency of novel BCR-ABLT315I inhibitors as an alternative to ponatinib

Gomari

Rostami

Ghodrati

et al. 2021

Computational Toxicology

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Discovery of Novel DUSP4 Inhibitors through the Virtual Screening with Docking Simulations

Cited by 7 publications

References 23 publications

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

Cyclooxygenase 2-Regulated Genes an Alternative Avenue to the Development of New Therapeutic Drugs for Colorectal Cancer

Mitogen-Activated Protein Kinase Phosphatases: No Longer Undruggable?

Implementation of docking, molecular dynamics and free energy to investigate drug potency of novel BCR-ABLT315I inhibitors as an alternative to ponatinib

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