Dataset Information

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

ABSTRACT: In this study we aimed to identify off-targets of polo-like kinase 1 (Plk1) small molecule inhibitor volasertib. Plk1 is an important cell cycle kinase and an attractive target for anticancer treatment. Volasertib is ATP-competitive small molecules that may also block the ATP-pocket of other proteins. Despite the fatal infections and negative survival in a phase III trial on volasertib in acute myeloid leukemia volasertib has been a promising treatment option in children with rhabdomyosarcoma. Therefore, there is a need to understand the nature of adverse effects that possibly originate from the off-target proteins. We used thermal proteome profiling (TPP) to identify proteins that have a change in the thermal stability after treatment with volasertib. The temperature of aggregation of several proteins involved in prostaglandin and phosphatidyl-inositol phosphate metabolism increased after treatment with volasertib. PIP4K2A and ZADH2 were stabilized both by treatment in living cells and cell lysate. Functional disruption of these proteins affects the immune response and fatty acid metabolism. In addition, volasertib was found to affect transcriptional coactivators, normal and alternative RNA splicing regulators and proteins involved in the intracellular transport regulation. Our data suggests that the identified proteins may contribute more to the understanding of anti-tumor effect of volasertib.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Rozbeh Jafari

LAB HEAD: Rozbeh Jafari

PROVIDER: PXD023757 | Pride | 2021-08-23

REPOSITORIES: Pride

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Publications

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off-targets of Polo-like kinase 1 inhibitor volasertib.

Goroshchuk Oksana O Kolosenko Iryna I Kunold Elena E Vidarsdottir Linda L Pirmoradian Mohammad M Azimi Alireza A Jafari Rozbeh R Palm-Apergi Caroline C

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20210701 7

Polo-like kinase 1 (PLK1) is an important cell cycle kinase and an attractive target for anticancer treatments. An ATP-competitive small molecular PLK1 inhibitor, volasertib, has reached phase III in clinical trials in patients with refractory acute myeloid leukemia as a combination treatment with cytarabine. However, severe side effects limited its use. The origin of the side effects is unclear and might be due to insufficient specificity of the drug. Thus, identifying potential off-targets to ...[more]

PMID: 34143546

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Dataset Information

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

Publications

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off-targets of Polo-like kinase 1 inhibitor volasertib.

Similar Datasets

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