PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, inhibits anaplastic thyroid carcinoma cell proliferation and migration

Che, Huan-yong; Guo, Hangyuan; Si, Xu-wei; Qin, You; Lou, Wei-ying

doi:10.1007/s13277-014-2118-3

Cited by 20 publications

(13 citation statements)

References 22 publications

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“…Ibrutinib is one common ligand for both BPAG1 and MACF1, and is used clinically for the treatment of lymphoma and leukemia [ 144 , 145 ]. PP121, showing antitumorigenic effects on esophageal cancer and anaplastic thyroid carcinoma by perturbing PI3K and mammalian target of rapamycin (mTOR) kinase activities [ 146 , 147 ], is identified as an MACF1 ligand. Moreover, plectin is determined to be a substrate for sparsomycin, pactamycin, amicoumacin A, and omacetaxine mepesuccinate, all of which show antitumorigenic effects in leukemia, HNSCC, breast cancer, or lung cancer [ 148 , 149 , 150 , 151 ].…”

Section: Mammalian Plakins In Human Cancermentioning

confidence: 99%

Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer

Huang

et al. 2018

IJMS

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Cancer is a highly lethal disease that is characterized by aberrant cell proliferation, migration, and adhesion, which are closely related to the dynamic changes of cytoskeletons and cytoskeletal-adhesion. These will further result in cell invasion and metastasis. Plakins are a family of giant cytolinkers that connect cytoskeletal elements with each other and to junctional complexes. With various isoforms composed of different domain structures, mammalian plakins are broadly expressed in numerous tissues. They play critical roles in many cellular processes, including cell proliferation, migration, adhesion, and signaling transduction. As these cellular processes are key steps in cancer development, mammalian plakins have in recent years attracted more and more attention for their potential roles in cancer. Current evidence shows the importance of mammalian plakins in various human cancers and demonstrates mammalian plakins as potential biomarkers for cancer. Here, we introduce the basic characteristics of mammalian plakins, review the recent advances in understanding their biological functions, and highlight their roles in human cancers, based on studies performed by us and others. This will provide researchers with a comprehensive understanding of mammalian plakins, new insights into the development of cancer, and novel targets for cancer diagnosis and therapy.

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Section: Mammalian Plakins In Human Cancermentioning

confidence: 99%

Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer

Huang

et al. 2018

IJMS

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“…PP121 was developed as a dual inhibitor of tyrosine kinases and phosphoinositide 3-kinases (PI3Ks) ( 27 ) and was shown to inhibit PI3Ks, RTKs, and Src family kinases. PP121 was reported to block the proliferation of glioblastoma, thyroid, and other tumor cells and inhibit multiple, oncogenic or mutated kinases ( 28 ). SC-1, also known as pluripotin, inhibits Erk1 (MAPK3) and RasGAP (RASA1) and blocks differentiation pathways in embryonic stem cells, although its kinase inhibition profile demonstrates broader activity against many tyrosine kinases ( 11 , 29 ).…”

Section: Resultsmentioning

confidence: 99%

Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer

Bello

Paindelli

Díaz-Gómez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Castration-resistant prostate cancer (CRPC) is an advanced subtype of prostate cancer with limited therapeutic options. Here, we applied a systems-based modeling approach called kinome regularization (KiR) to identify multitargeted kinase inhibitors (KIs) that abrogate CRPC growth. Two predicted KIs, PP121 and SC-1, suppressed CRPC growth in two-dimensional in vitro experiments and in vivo subcutaneous xenografts. An ex vivo bone mimetic environment and in vivo tibia xenografts revealed resistance to these KIs in bone. Combining PP121 or SC-1 with docetaxel, standard-of-care chemotherapy for late-stage CRPC, significantly reduced tibia tumor growth in vivo, decreased growth factor signaling, and vastly extended overall survival, compared to either docetaxel monotherapy. These results highlight the utility of computational modeling in forming physiologically relevant predictions and provide evidence for the role of multitargeted KIs as chemosensitizers for late-stage, metastatic CRPC.

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“…A systematic effort to discover inhibitors that potently inhibit both TKs and PI3Ks led to the discovery of the novel multitargeted tool inhibitor PP121 [37]. This broadly active compound blocked the proliferation of tumor cells [38]. Hesperadin was discovered to be a potent inhibitor of chromosome alignment and segregation [39].…”

Section: Resultsmentioning

confidence: 99%

Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity

Ahmad

Johnson

Scott

2015

Biochemical and Biophysical Research Communications

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The kinase MEKK2 (MAP3K2) may play an important role in tumor growth and metastasis for several cancer types. Thus, targeting MEKK2 may represent a novel strategy for developing more effective therapies for cancer. In order to identify small molecules with MEKK2 inhibitory activity, we screened a collection of known kinase inhibitors using a high throughput MEKK2 intrinsic ATPase enzyme assay and confirmed activity of the most potent hits with this primary assay. We also confirmed activities of these known kinase inhibitors with an MEKK2 transphosphorylation slot blot assay using MKK6 as a substrate. We observed a good correlation in potencies between the two orthogonal MEKK2 kinase activity assay formats for this set of inhibitors. We report that ponatinib, AT9283, AZD7762, JNJ-7706621, PP121 and hesperadin had potent MEKK2 enzyme inhibitory activities ranging from 4.7 – 60 nM IC50. Ponatinib is an FDA-approved drug that potently inhibited MEKK2 enzyme activity with IC50 values of 10 – 16 nM. AT9283 is currently in clinical trials and produced MEKK2 IC50 values of 4.7 – 18 nM. This set of known kinase inhibitors represents some of the most potent in vitro MEKK2 inhibitors reported to date and may be useful as research tools. Although these compounds are not selective for MEKK2, the structures of these compounds give insight into pharmacophores that potently inhibit MEKK2 and could be used as initial leads to design highly selective inhibitors of MEKK2.

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PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, inhibits anaplastic thyroid carcinoma cell proliferation and migration

Cited by 20 publications

References 22 publications

Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer

Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer

Computational modeling identifies multitargeted kinase inhibitors as effective therapies for metastatic, castration-resistant prostate cancer

Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity

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