Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

Simple item page
dc.contributor.authorNajjar, Malek
dc.contributor.authorSuebsuwong, Chalada
dc.contributor.authorRay, Soumya S.
dc.contributor.authorThapa, Roshan J.
dc.contributor.authorMaki, Jenny L.
dc.contributor.authorNogusa, Shoko
dc.contributor.authorShah, Saumil
dc.contributor.authorSaleh, Danish
dc.contributor.authorGough, Peter J.
dc.contributor.authorBertin, John
dc.contributor.authorYuan, Junying
dc.contributor.authorBalachandran, Siddharth
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorDegterev, Alexei
dc.date.accessioned2020-03-10T17:32:10Z
dc.date.available2020-03-10T17:32:10Z
dc.date.issued2015-03
dc.description.abstractRIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory tumor necrosis factor alpha (TNF-?) gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective “hybrid” RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1- and RIPK3-driven inflammatory pathologies.
dc.identifier.citationCopyright 2015 Cell Reports. Recommended citation: Najjar, Malek, Chalada Suebsuwong, Soumya S. Ray, Roshan J. Thapa, Jenny L. Maki, Shoko Nogusa, Saumil Shah et al. "Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1." Cell reports 10, no. 11 (2015): 1850-1860. doi: 10.1016/j.celrep.2015.02.052. URL:https://www.sciencedirect.com/science/article/pii/S2211124715002107. Reproduced in accordance with the original publisher's licensing terms and with permission from the authors.
dc.identifier.urihttps://hdl.handle.net/10657/5975
dc.language.isoen_US
dc.publisherCell Reports
dc.titleStructure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1
dc.typeArticle

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
Cuny_2015_StructureGuidedDesign.pdf
Size:
2.96 MB
Format:
Adobe Portable Document Format
Download

License bundle

Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
4.69 KB
Format:
Plain Text
Description:
Download

Collections

UH Faculty, Staff, and Student Works