Discovery of thiophene inhibitors of polo-like kinase

Emmitte, Kyle A.; Andrews, Chandler; Badiang, Jennifer G.; Davis‐Ward, Ronda G.; Dickson, Hamilton D.; Drewry, David H.; Emerson, Holly K.; Epperly, Andrea H.; Hassler, Daniel F.; Knick, Victoria B.; Kuntz, Kevin W.; Lansing, Timothy J.; Linn, James A.; Mook, Robert A.; Nailor, Kristen E.; Salovich, James M.; Spehar, Glenn; Cheung, Mui

doi:10.1016/j.bmcl.2008.11.041

Cited by 32 publications

(25 citation statements)

References 13 publications

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“…GSK461364A was identified after a library screening campaign using a Plk1 scintillation proximity assay, accompanied by lead optimization of the identified chemical entity (structure/ activity relationship), leading to the identification of GSK461364A (32). When evaluated against full-length Plk1 in an in vitro biochemical assay, inclusion of a 60-minute preincubation step significantly increased the compound potency ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

et al. 2009

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Polo-like kinase 1 (Plk1) is a conserved serine/threonine kinase that plays an essential role in regulating the many processes involved in mitotic entry and progression. In humans, Plk1 is expressed primarily during late G 2 and M phases and, in conjunction with Cdk1/cyclin B1, acts as master regulatory kinases for the myriad protein substrates involved in mitosis. Plk1 overexpression is strongly associated with cancer and has been correlated with poor prognosis in a broad range of human tumor types. We have identified a potent, selective, reversible, ATP-competitive inhibitor of Plk1,

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Section: Resultsmentioning

confidence: 99%

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

et al. 2009

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“…GSK461364A is a thiophene-derived compound that is shown to competitively inhibit the ATP-binding site of Plk1 with a high potency [90, 109]. Remarkably, it shows an enhanced antitumor effect in cancer cells where p53 is downregulated or mutated [69].…”

Section: Targeting the Catalytic Domain Of Plk1mentioning

confidence: 99%

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Lee

Burke

Park

et al. 2015

Trends in Pharmacological Sciences

107

134

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Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are critical for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of certain cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic domain, which phosphorylates substrates, and the C-terminal polo-box domain, which is essential for protein–protein interactions. In this review, we will summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We will also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders.

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“…This broad kinase inhibitiory effect of scytonemin suggests that this compound decreases cell proliferation and increases apoptosis in a cell-cycle-independent manner. This does not appear to be in line with the specific Plk1 inhibition where a strong G 2 /M cell cycle arrest leads to apoptosis in cancer cells (36,50,51,54). …”

Section: Negative Regulation Of Plk1 By Natural Agents: Plk1 As a Tarmentioning

confidence: 81%

Modulating Polo-Like Kinase 1 as a Means for Cancer Chemoprevention

2010

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Naturally occurring agents have always been appreciated for their medicinal value for both their chemopreventive and therapeutic effects against cancer. In fact, the majority of the drugs we use today, including the anti-cancer agents, were originally derived from natural compounds, either in their native form or modified to enhance their bioavailability or specificity. It is believed that for maximum effectiveness, it will useful to design novel target-based agents for chemoprevention as well as the treatment of cancer. Recent studies have shown that the serine/threonine kinase polo-like kinase (Plk) 1 is widely overexpressed in a variety of cancers and is being increasingly appreciated as a target for cancer management. Additionally, several chemopreventive agents have been shown to inhibit Plk1 in cancer cells. In this review, we will discuss if Plk1 could also be a target for designing novel strategies for cancer chemoprevention.

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Discovery of thiophene inhibitors of polo-like kinase

Cited by 32 publications

References 13 publications

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

Distinct Concentration-Dependent Effects of the Polo-like Kinase 1–Specific Inhibitor GSK461364A, Including Differential Effect on Apoptosis

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Modulating Polo-Like Kinase 1 as a Means for Cancer Chemoprevention

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