Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase Inhibitors Article Swipe
Dennis X. Hu
,
Snahel Patel
,
Huifen Chen
,
Shu‐Mei Wang
,
Steven T. Staben
,
Yoana N. Dimitrova
,
Heidi Ackerly Wallweber
,
Joanna Y. Lee
,
Grace Ka Yan Chan
,
Christopher J. Sneeringer
,
Madeleine Prangley
,
John G. Moffat
,
Kai Wu
,
Leah Schutt
,
Laurent Salphati
,
Jodie Pang
,
Erin McNamara
,
Haochu Huang
,
Yong Chen
,
Yunli Wang
,
Wensheng Zhao
,
Junghyun Lim
,
Aditya Murthy
,
Michael Siu
·
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.1c01180
YOU?
·
· 2021
· Open Access
·
· DOI: https://doi.org/10.1021/acs.jmedchem.1c01180
VPS34 is a class III phosphoinositide 3-kinase involved in endosomal trafficking and autophagosome formation. Inhibitors of VPS34 were believed to have value as anticancer agents, but genetic and pharmacological data suggest that sustained inhibition of VPS34 kinase activity may not be well tolerated. Here we disclose the identification of a novel series of dihydropyrazolopyrazinone compounds represented by compound 5 as potent, selective, and orally bioavailable VPS34 inhibitors through a structure-based design strategy. A water-interacting hydrogen bond acceptor within an appropriate distance to a hinge-binding element was found to afford significant VPS34 potency across chemical scaffolds. The selectivity of compound 5 over PIK family kinases arises from interactions between the hinge-binding element and the pseudo-gatekeeper residue Met682. As recent in vivo pharmacology data suggests that sustained inhibition of VPS34 kinase activity may not be tolerated, structure-activity relationships leading to VPS34 inhibition may be helpful for avoiding this target in other ATP-competitive kinase programs.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1021/acs.jmedchem.1c01180
- OA Status
- green
- Cited By
- 19
- References
- 33
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3213556903
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3213556903Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1021/acs.jmedchem.1c01180Digital Object Identifier
- Title
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Structure-Based Design of Potent, Selective, and Orally Bioavailable VPS34 Kinase InhibitorsWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2021Year of publication
- Publication date
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2021-11-15Full publication date if available
- Authors
-
Dennis X. Hu, Snahel Patel, Huifen Chen, Shu‐Mei Wang, Steven T. Staben, Yoana N. Dimitrova, Heidi Ackerly Wallweber, Joanna Y. Lee, Grace Ka Yan Chan, Christopher J. Sneeringer, Madeleine Prangley, John G. Moffat, Kai Wu, Leah Schutt, Laurent Salphati, Jodie Pang, Erin McNamara, Haochu Huang, Yong Chen, Yunli Wang, Wensheng Zhao, Junghyun Lim, Aditya Murthy, Michael SiuList of authors in order
- Landing page
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https://doi.org/10.1021/acs.jmedchem.1c01180Publisher landing page
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://doi.org/10.7270/q2zc86xqDirect OA link when available
- Concepts
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Chemistry, Kinase, In vivo, Protein kinase A, Stereochemistry, Biochemistry, Biology, GeneticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
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19Total citation count in OpenAlex
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2025: 2, 2024: 6, 2023: 7, 2022: 4Per-year citation counts (last 5 years)
- References (count)
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33Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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