Development and Therapeutic Potential of NUAKs Inhibitors

Faisal, Muhammad; Kim, Jae Ho; Yoo, Kyung Ho; Roh, Eun Joo; Hong, Soon‐Sun; Lee, So Ha

doi:10.1021/acs.jmedchem.0c00533

Cited by 19 publications

(22 citation statements)

References 132 publications

(372 reference statements)

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“…36 As another potential medicinal chemistry strategy, several compounds have been documented to have off-target NUAK2 activity and may serve as starting scaffolds for new compound optimization campaigns. 12 Yet, as is, results with HTH-02-006 as a NUAK2 inhibitor coupled with genetic studies, Mechanistically, our studies confirm that in PC, NUAK2 also acts on the core components of the Hippo phosphorylation cascade to regulate the downstream transcriptional coactivators, YAP and TAZ as previously described. 15 As in liver cancer, our data suggest that in PC NUAK2 itself is a target gene of YAP and by inhibiting the LATS-mediated inactivation of YAP, NUAK2 effectively acts in a feed forward loop with YAP (Figure 6D).…”

Section: Discussionsupporting

confidence: 89%

“…10,11 NUAK2 has been reported to play a role in several cancer types, but studies on NUAK2 in PC are lacking. 12 In melanoma, NUAK2 gene amplification is coupled with PTEN deficiency and higher NUAK2 expression correlates with worse prognosis. 13 Additionally, recent studies have shown that NUAK2 has protumorigenic roles in breast cancer and hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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NUAK family kinase 2 is a novel therapeutic target for prostate cancer

Zhao

Driver

et al. 2021

Molecular Carcinogenesis

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Current advancements in prostate cancer (PC) therapies have been successful in slowing PC progression and increasing life expectancy; however, there is still no curative treatment for advanced metastatic castration resistant PC (mCRPC). Most treatment options target the androgen receptor, to which many PCs eventually develop resistance. Thus, there is a dire need to identify and validate new molecular targets for treating PC. We found NUAK family kinase 2 (NUAK2) expression is elevated in PC and mCRPC versus normal tissue, and expression correlates with an increased risk of metastasis. Given this observation and because NUAK2, as a kinase, is actionable, we evaluated the potential of NUAK2 as a molecular target for PC.NUAK2 is a stress response kinase that also plays a role in activation of the YAP cotranscriptional oncogene. Combining pharmacological and genetic methods for modulating NUAK2, we found that targeting NUAK2 in vitro leads to reduction in proliferation, three-dimensional tumor spheroid growth, and matrigel invasion of PC cells. Differential gene expression analysis of PC cells treated NUAK2 small molecule inhibitor HTH-02-006 demonstrated that NUAK2 inhibition results in downregulation of E2F, EMT, and MYC hallmark gene sets after NUAK2 inhibition. In a syngeneic allograft model and in radical prostatectomy patient derived explants, NUAK2 inhibition slowed tumor growth and proliferation rates. Mechanistically, HTH-02-006 treatment led to inactivation of YAP and the downregulation of NUAK2 and MYC protein levels. Our results suggest that NUAK2 represents a novel actionable molecular target for PC that warrants further exploration.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

NUAK family kinase 2 is a novel therapeutic target for prostate cancer

Zhao

Driver

et al. 2021

Molecular Carcinogenesis

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“…These kinases include some of the original targets for which pyrimidine-based inhibitors were prepared (JAK2, IKKε, TBK1, and ULK1), a more well-studied kinase that is potently inhibited by many analogs within this structural class (AURKB), and several understudied kinases, many of which are both on the IDG list (AAK1, BMP2K, DRAK1−2, MARK1−4, MLK1, MLK3, and NUAK1) and of interest in the neuroscience space. 14,15,17,[26][27][28][29] We profiled our pyrimidine series and the parent pyrimidines that influenced our design against this kinase panel at a single concentration (1 μM) in radiometric enzymatic assays at Eurofins at the Km = ATP for each kinase. Table 1 shows the results of this study, where % control is reported for each compound for each kinase and lower values indicate greater inhibition.…”

Section: Resultsmentioning

confidence: 99%

Strategy for Lead Identification for Understudied Kinases

Drewry¹,

Jk²,

Wells³

et al. 2021

Preprint

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<p>In our manuscript we outline an approach in which we convert a promiscuous pyrimidine scaffold into narrowly selective, cell-active chemical leads for several understudied kinases, including DRAK1, BMP2K, and MARK4. These chemical tools will allow illumination of the function(s) of these poorly characterized kinases for the first time. Several of the understudied kinases that we inhibit with our pyrimidine-based compounds are also implicated in neurodegenerative disease, pushing the utility of kinase inhibitors outside of the oncology space and offering opportunities for the validation of therapeutic hypotheses attributed to these kinases.</p>

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“…Both WZ4003 and HTH-01-015 are presumed to act as ATPcompetitive inhibitors, but their precise mechanism of action is unknown. Over the last few years additional NUAK inhibitors have been described [51], but to date a specific NUAK2 inhibitor has not been generated. Peptide decoys could possibly be utilized to maximize specificity.…”

Section: Selective Nuak Inhibitorsmentioning

confidence: 99%

NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

Vis

Moustakas

Heide

2021

Cancers

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Transforming growth factor-β (TGF-β) signaling plays a key role in governing various cellular processes, extending from cell proliferation and apoptosis to differentiation and migration. Due to this extensive involvement in the regulation of cellular function, aberrant TGF-β signaling is frequently implicated in the formation and progression of tumors. Therefore, a full understanding of the mechanisms of TGF-β signaling and its key components will provide valuable insights into how this intricate signaling cascade can shift towards a detrimental course. In this review, we discuss the interplay between TGF-β signaling and the AMP-activated protein kinase (AMPK)-related NUAK kinase family. We highlight the function and regulation of these kinases with focus on the pivotal role NUAK1 and NUAK2 play in regulating TGF-β signaling. Specifically, TGF-β induces the expression of NUAK1 and NUAK2 that regulates TGF-β signaling output in an opposite manner. Besides the focus on the TGF-β pathway, we also present a broader perspective on the expression and signaling interactions of the NUAK kinases to outline the broader functions of these protein kinases.

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Development and Therapeutic Potential of NUAKs Inhibitors

Cited by 19 publications

References 132 publications

NUAK family kinase 2 is a novel therapeutic target for prostate cancer

NUAK family kinase 2 is a novel therapeutic target for prostate cancer

Strategy for Lead Identification for Understudied Kinases

NUAK1 and NUAK2 Fine-Tune TGF-β Signaling

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