MKI-1, a Novel Small-Molecule Inhibitor of MASTL, Exerts Antitumor and Radiosensitizer Activities Through PP2A Activation in Breast Cancer

Kim, Ah-young; Yoon, Yi Na; Leem, Jiyeon; Lee, Jee Young; Jung, Kwan‐Young; Kang, Minsung; Ahn, Joon-Woo; Hwang, Sang‐Gu; Oh, Jeong Su; Kim, Jae-Sung

doi:10.3389/fonc.2020.571601

Cited by 12 publications

(33 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PP2A hyperphosphorylation, as well as upregulation of the endogenous PP2A inhibitors such as SET, has been reported as main molecular mechanisms of PP2A inhibition in many tumors including breast cancer. These alterations have progressively emerged as promising therapeutic targets in this disease [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Although it has been recently reported that PP2A inhibition is a frequent alteration in breast cancer related with poor outcome and therapy resistance, such studies have been carried out in cohorts including cases with different molecular subtypes [ 40 , 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Sanz-Álvarez

Cristóbal

Luque

et al. 2021

Cancers

View full text Add to dashboard Cite

The bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal domain (BET) protein family, has emerged in the last years as a promising molecular target in many tumors including breast cancer. The triple negative breast cancer (TNBC) represents the molecular subtype with the worst prognosis and a current therapeutic challenge, and TNBC cells have been reported to show a preferential sensitivity to BET inhibitors. Interestingly, BRD4 phosphorylation (pBRD4) was found as an alteration that confers resistance to BET inhibition and PP2A proposed as the phosphatase responsible to regulate pBRD4 levels. However, the potential clinical significance of pBRD4, as well as its potential correlation with the PP2A pathway in TNBC, remains to be investigated. Here, we evaluated the expression levels of pBRD4 in a series of 132 TNBC patients. We found high pBRD4 levels in 34.1% of cases (45/132), and this alteration was found to be associated with the development of patient recurrences (p = 0.007). Interestingly, BRD4 hyperphosphorylation predicted significantly shorter overall (p < 0.001) and event-free survival (p < 0.001). Moreover, multivariate analyses were performed to confirm its independent prognostic impact in our cohort. In conclusion, our findings show that BRD4 hyperphosphorylation is an alteration associated with PP2A inhibition that defines a subgroup of TNBC patients with unfavorable prognosis, suggesting the potential clinical and therapeutic usefulness of the PP2A/BRD4 axis as a novel molecular target to overcome resistance to treatments based on BRD4 inhibition.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Sanz-Álvarez

Cristóbal

Luque

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Notably, MASTL are highly expressed in multiple types of cancers, including breast, head and neck, gastric, thyroid, and colorectal cancers [ 12 , 15 , 17 , 18 , 19 , 20 ]. MASTL inhibition selectively eradicated proliferative cancer cells rather than normal cells by inducing mitotic catastrophe [ 12 , 21 , 22 ]. Therefore, accumulating evidence clearly indicates that MASTL is an attractive, druggable target for selective anticancer treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several groups reported candidate compounds as potential MASTL inhibitors [ 22 , 23 , 24 ]. Greatwall kinase inhibitor-1 (GKI-1) was reported as a first-line inhibitor against MASTL, which was designed by using the solved protein structure of the kinase domain of MASTL [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…GKI-1 can inhibit MASTL in vitro and disrupt mitotic events by decreasing phosphorylated ENSA with μM range potency in HeLa cells [ 23 ]. However, GKI-1 did not show the anticancer activity in breast cancer cells [ 22 ]. Further, two compounds identified in silico in another study could be potential MASTL inhibitors without any validated biochemical data [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further, two compounds identified in silico in another study could be potential MASTL inhibitors without any validated biochemical data [ 24 ]. We previously reported MASTL kinase inhibitor-1 (MKI-1), a new MASTL inhibitor, showing antitumor activities across in vitro and in vivo tumor models by inhibiting MASTL in breast cancer cells [ 22 ]. Nonetheless, MKI-1 also showed μM range potency and efficacy for MASTL inhibition [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes

et al. 2021

Self Cite

View full text Add to dashboard Cite

Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico through a drug discovery program. Our data showed that MKI-2 inhibited recombinant MASTL activity and cellular MASTL activity with IC50 values of 37.44 nM and 142.7 nM, respectively, in breast cancer cells. In addition, MKI-2 inhibited MASTL kinase rather than other AGC kinases, such as ROCK1, AKT1, PKACα, and p70S6K. Furthermore, MKI-2 exerted various antitumor activities by inducing mitotic catastrophe resulting from the modulation of the MASTL-PP2A axis in breast cancer cells. The MKI-2 treatment showed phenocopies with MASTL-null oocyte in mouse oocytes, which were used as a model to validate MKI-2 activity. Therefore, our study provided a new potent and selective MASTL inhibitor MKI-2 targeting the oncogenic MAST-PP2A axis in breast cancer cells.

show abstract

Therapeutic natural compounds Enzastaurin and Palbociclib inhibit MASTL kinase activity preventing breast cancer cell proliferation

Polisety¹,

Misra²,

Rajawat

et al. 2022

Med Oncol

View full text Add to dashboard Cite

Microtubule-associated serine/threonine kinase-like (MASTL) regulates mitotic progression and is an attractive target for the development of new anticancer drugs. In this study, novel inhibitory molecules were screened against MASTL kinase, a protein involved in cell proliferation in breast cancer. Natural source-derived drugs Enzastaurin and Palbociclib were selected to identify their role as MASTL kinase inhibitors. Cytotoxic activity, kinase activity, and other cell-based assays of Enzastaurin and Palbociclib were evaluated on human breast cancer (MCF-7) cells. The potential natural compounds caused cytotoxicity in MCF-7 cells in a dose- and time-dependent manner. Further analysis by Annexin V and PI staining indicated that both drugs are potent inducers of apoptosis. Enzastaurin induced G2/M phase arrest, while Palbociclib caused G1 arrest. MASTL kinase activity was significantly abrogated with both the compounds showing EC 50 values of 17.13 µM and 10.51 µM, respectively. Taken together, these data strongly suggest that Enzastaurin and Palbociclib possess the ability to inhibit MASTL kinase activity and induce cell death in breast cancer cells, thus exhibiting significant therapeutic potential. Supplementary Information The online version contains supplementary material available at 10.1007/s12032-022-01701-3.

show abstract

MKI-1, a Novel Small-Molecule Inhibitor of MASTL, Exerts Antitumor and Radiosensitizer Activities Through PP2A Activation in Breast Cancer

Cited by 12 publications

References 43 publications

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Expression of Phosphorylated BRD4 Is Markedly Associated with the Activation Status of the PP2A Pathway and Shows a Strong Prognostic Value in Triple Negative Breast Cancer Patients

Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes

Therapeutic natural compounds Enzastaurin and Palbociclib inhibit MASTL kinase activity preventing breast cancer cell proliferation

Contact Info

Product

Resources

About