학술논문
The small molecule inhibitor NAV-2729 has a complex target profile including multiple ADP-ribosylation factor regulatory proteins.
Document Type
Academic Journal
Author
Rosenberg EM Jr; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Jian X; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Soubias O; Center for Structural Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.; Yoon HY; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Yadav MP; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Hammoudeh S; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Pallikkuth S; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Akpan I; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Chen PW; Department of Biology, Williams College, Williamstown, Massachusetts, USA.; Maity TK; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Jenkins LM; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.; Yohe ME; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA; Laboratory of Cell and Developmental Signaling, Center for Cancer Research, Frederick, Maryland, USA.; Byrd RA; Center for Structural Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.; Randazzo PA; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. Electronic address: randazzp@mail.nih.gov.
Source
Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE
Subject
Language
English
Abstract
The ADP-ribosylation factor (Arf) GTPases and their regulatory proteins are implicated in cancer progression. NAV-2729 was previously identified as a specific inhibitor of Arf6 that reduced progression of uveal melanoma in an orthotopic xenograft. Here, our goal was to assess the inhibitory effects of NAV-2729 on the proliferation of additional cell types. We found NAV-2729 inhibited proliferation of multiple cell lines, but Arf6 expression did not correlate with NAV-2729 sensitivity, and knockdown of Arf6 affected neither cell viability nor sensitivity to NAV-2729. Furthermore, binding to native Arf6 was not detected; however, we determined that NAV-2729 inhibited both Arf exchange factors and Arf GTPase-activating proteins. ASAP1, a GTPase-activating protein linked to cancer progression, was further investigated. We demonstrated that NAV-2729 bound to the PH domain of ASAP1 and changed ASAP1 cellular distribution. However, ASAP1 knockdown did not fully recapitulate the cytoskeletal effects of NAV-2729 nor affect cell proliferation. Finally, our screens identified 48 other possible targets of NAV-2729. These results illustrate the complexities of defining targets of small molecules and identify NAV-2729 as a model PH domain-binding inhibitor.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Published by Elsevier Inc.)
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Published by Elsevier Inc.)