Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)

Nie, Zhe; Feher, Victoria A.; Natala, Srinivasa Reddy; McBride, Christopher M.; Kir'yanov, A. A.; Jones, Benjamin; Lam, Betty; Liu, Yan; Kaldor, Stephen W.; Stafford, Jeffrey A.; Hikami, Kouki; Uchiyama, Noriko; Kawamoto, Takahiro; Hikichi, Yuichi; Matsumoto, Shimpei; Amano, Nobuyuki; Zhang, Lilly; Hosfield, David J.; Skene, R.J.; Zou, Hua; Cao, Xiaodong; Ichikawa, Takashi

doi:10.1016/j.bmcl.2013.02.083

Cited by 41 publications

(26 citation statements)

References 30 publications

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“…17 Our results now broaden these finding and indicate that TAK-960 is an extremely potent inhibitor of sarcoma cell growth. We further show with siRNA that the antiproliferative effect of TAK-960 is a result of target specific inhibition of PLK-1.…”

Section: Discussionsupporting

confidence: 69%

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Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Nair

Schwartz

2015

Cell Cycle

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Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK-960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with downregulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts. In the setting of PLK-1 inhibition, Mcl-1 down regulation is shown to be an important determinant of apoptosis. Collectively, the net effect of this is to drive cells to apoptosis, resulting in a greater anti-tumor effect in vivo. Therefore, targeting PLK-1 should have a greater impact in treating sarcomas provided there is concomitant suppression of Mcl-1. These results further indicate that Mcl-1 could be an important biomarker to predict sensitivity to the induction of apoptosis by PLK-1 targeted therapy in sarcoma.

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Section: Discussionsupporting

confidence: 69%

“…TAK-960 is an investigational PLK1 inhibitor that binds to the ATP-binding pocket of PLK1. 17,18 It is an orally bioavailable, potent and selective PLK1 inhibitor. It has been shown to exhibit single-agent antitumor activity in a variety of tumor cell lines, xenograft models of solid tumors and hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Nair

Schwartz

2015

Cell Cycle

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“…Still, other clinical phase I/II trials are being conducted in patients with several types of cancer to monitor both drugs' efficacy and safety. Over recent years, a considerable number of other PLK1 inhibitors with different mechanisms of actions (ATP competitors, substrate competitors that bind to the polo-box domain or bifunctional compounds that compete simultaneously with ATP, and the peptide or protein substrate for their respective binding sites) have been developed [52][53][54][55][56], most of which show broad-spectrum preclinical antitumor activity. In turn, some of them might result in lower toxicity and may become standard therapeutics that will improve treatment outcome for many tumors.…”

Section: Discussionmentioning

confidence: 99%

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments

Bogado

Pezuk²,

Oliveira³

et al. 2015

Anti-Cancer Drugs

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Polo-like kinase 1 (PLK1), a key regulator of mitosis, is often overexpressed in childhood cancers and is associated with poor prognosis. Previous reports have shown that inhibition of PLK1 might serve as a promising anticancer treatment for osteosarcoma. In this study, we tested the second-generation PLK1 inhibitors BI 6727 and GSK461364 in HOS and MG-63 cell lines, both as a single agent and in combination with methotrexate, cisplatin, vinblastine, doxorubicin, or ionizing radiation. Both PLK1 inhibitors worked equally in terms of cell growth arrest, apoptosis induction, and radiosensitization. Combining BI 6727 or GSK461364 with conventional treatments, however, showed trivial synergistic antitumor effects in vitro. Our results reinforce the potential use of PLK1 inhibitors for a pharmacologic intervention in osteosarcoma, although their applicability in polychemotherapeutic regimens deserves further investigation.

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“…These drugs are starting to be explored, so not much information is available on them. One such agent, Tak 960, was discovered through optimization of a novel series of pyrimidodiazepinone Plk1 inhibitors (73). Tak960 has an IC50 of 2 nmol/L, and a study in HT-29 colorectal cells found that they were arrested in G2-M phase when treated with Tak960 (74).…”

Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

338

272

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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Discovery of TAK-960: An orally available small molecule inhibitor of polo-like kinase 1 (PLK1)

Cited by 41 publications

References 30 publications

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression

BI 6727 and GSK461364 suppress growth and radiosensitize osteosarcoma cells, but show limited cytotoxic effects when combined with conventional treatments

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

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