2018
DOI: 10.1002/cmdc.201700779
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Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain

Abstract: The wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types. Because of its negative role in regul… Show more

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Cited by 9 publications
(13 citation statements)
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“…This class of genes may offer unique opportunities to impede the development of CH. For example, because PPM1D acts dominantly, there have been efforts to develop inhibitors 55 that may offer an opportunity to slow clonal expansion. An improved understanding of the mechanisms and opportunities may drive different choices of chemotherapeutic agents in contexts where CH or secondary malignancies may be deemed a particular risk.…”
Section: Ddr Regulators In Chmentioning
confidence: 99%
“…This class of genes may offer unique opportunities to impede the development of CH. For example, because PPM1D acts dominantly, there have been efforts to develop inhibitors 55 that may offer an opportunity to slow clonal expansion. An improved understanding of the mechanisms and opportunities may drive different choices of chemotherapeutic agents in contexts where CH or secondary malignancies may be deemed a particular risk.…”
Section: Ddr Regulators In Chmentioning
confidence: 99%
“…Although inhibition of WIP1 by GSK2830371 is highly potent in vitro (IC 50 = 6 n m ) with good efficacy in WT P53 tumor cell lines, the compound exhibits poor pharmacokinetics with a short half-life in vivo (29). Unfortunately, attempts to overcome this problem through modification of the scaffold have resulted in reduced potency, with the chirality of the central l -cyclohexyl alanine moiety being crucial for the inhibitory activity (29, 30). Structure-activity relationship studies based on an analogue of GSK2830371 were performed at three positions of the scaffold.…”
Section: Discussionmentioning
confidence: 99%
“…Structure-activity relationship studies based on an analogue of GSK2830371 were performed at three positions of the scaffold. All modifications to the central position resulted in a complete loss of WIP1 inhibition, while a few modifications to the other positions, although tolerated, did not significantly improve the activity (30). Therefore, robust assays suitable for HTS are needed for the discovery of selective WIP1 inhibitors with improved pharmacokinetics.…”
Section: Discussionmentioning
confidence: 99%
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