Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Chao, Min Wu; Lin, Tony Eight; HuangFu, Wei Chun; Chang, Chia Chih; Tu, Huang Ju; Chen, Liang Chieh; Yen, Shih Chung; Sung, Tzu Ying; Huang, Wei; Yang, Congrong; Pan, Shiow Lin; Hsu, Kai Cheng

doi:10.1080/14756366.2020.1843452

Cited by 11 publications

(13 citation statements)

References 46 publications

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“…In this study, we identified novel target proteins involved in gentamicin-induced cytotoxicity using tandem mass spectrometry (MS/MS, referred to as MS from here on). We observed significant upregulation of TAO1 kinase in HEI-OC1, especially after treatment with high doses of gentamicin for 24 h. TAO-1 is a serine/threonine-protein kinase known to activate the MAPK cascade, regulating vital cellular processes such as mitosis, proliferation, differentiation, and immune responses [ 43 ]. Within the cell cycle, previous studies demonstrate that TAO-1 can shorten the G1 phase and skip a transient G0-like state to accelerate cell cycle progression [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Target Proteins Involved in Cochlear Hair Cell Progenitor Cytotoxicity following Gentamicin Exposure

Davies

Mittal

et al. 2022

JCM

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Given the non-labile, terminal differentiation of inner-ear sensory cells, preserving their function is critical since sensory cell damage results in irreversible hearing loss. Gentamicin-induced cytotoxicity is one of the major causes of sensory cell damage and consequent sensorineural hearing loss. However, the precise molecular mechanisms and target proteins involved in ototoxicity are still unknown. The objective of the present study was to identify target proteins involved in gentamicin-induced cytotoxicity to better characterize the molecular pathways involved in sensory cell damage following ototoxic drug administration using House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). We identified several unique proteins involved in gentamicin-induced cytotoxicity, expression of which were further confirmed using confocal microscopy. Further investigation of these pathways can inform the design and discovery of novel treatment modalities to prevent sensory cell damage and preserve their function.

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Section: Discussionmentioning

confidence: 99%

Identification of Target Proteins Involved in Cochlear Hair Cell Progenitor Cytotoxicity following Gentamicin Exposure

Davies

Mittal

et al. 2022

JCM

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“…A TAOK1 inhibitor has recently been described. Experiments using patient-derived ex vivo culture can determine whether small molecule inhibition of TAOK1 can impair tumor cell proliferation in human metastatic breast cancer 8 . Modulation of TAOK1 expression may be relevant to the processes by which breast cancer cells exit the breast, enter the vasculature and/or lymphatics, reside in the lymph nodes, evade immune clearance, breach the blood-brain barrier and colonize the brain.…”

Section: Discussionmentioning

confidence: 99%

TAOK1 is a differentially expressed gene in human metastatic breast cancer, in the brain and in the lymph nodes.

Mamoor¹

2021

Preprint

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Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that the TAO kinase 1, encoded by TAOK1, was among the genes whose expression was most different in the brain and lymph node metastases of patients with metastatic breast cancer. TAOK1 mRNA was present at increased quantities in brain metastatic tissues as compared to primary tumors of the breast. Importantly, expression of TAOK1 in primary tumors was significantly correlated with patient distant metastasis-free survival in patients with breast cancer. Modulation of TAOK1 expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain while evading immune clearance in the lymph nodes in humans with metastatic breast cancer. These data are one piece of evidence suggesting a common ancestor or tumor clone for brain and lymph node metastases that originate from the primary tumor, alluding to patterns in developmental origin and migratory pathways through the lymph node in human brain metastatic breast cancer.

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“…A sulforhodamine B (SRB) assay was used to measure the antiproliferative effect of a compound. The SRB assay was performed using a standard method as described previously 39 . Two pancreatic cancer cell lines were seeded in 96-well plates at a density of 5,000 cells per well overnight.…”

Section: Methodsmentioning

confidence: 99%

In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

Chang

Chao

Lee

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC 50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

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Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach

Cited by 11 publications

References 46 publications

Identification of Target Proteins Involved in Cochlear Hair Cell Progenitor Cytotoxicity following Gentamicin Exposure

Identification of Target Proteins Involved in Cochlear Hair Cell Progenitor Cytotoxicity following Gentamicin Exposure

TAOK1 is a differentially expressed gene in human metastatic breast cancer, in the brain and in the lymph nodes.

In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer

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