WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think
WDR5 is a conserved nuclear protein that scaffolds the assembly of epigenetic regulatory complexes and moonlights in functions ranging from recruiting MYC oncoproteins to chromatin to facilitating the integrity of mitosis. It is also a high-value target for anti-cancer therapies, with small molecule...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/13/1/274 |
| _version_ | 1797358544187555840 |
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| author | April M. Weissmiller Stephen W. Fesik William P. Tansey |
| author_facet | April M. Weissmiller Stephen W. Fesik William P. Tansey |
| author_sort | April M. Weissmiller |
| collection | DOAJ |
| description | WDR5 is a conserved nuclear protein that scaffolds the assembly of epigenetic regulatory complexes and moonlights in functions ranging from recruiting MYC oncoproteins to chromatin to facilitating the integrity of mitosis. It is also a high-value target for anti-cancer therapies, with small molecule WDR5 inhibitors and degraders undergoing extensive preclinical assessment. WDR5 inhibitors were originally conceived as epigenetic modulators, proposed to inhibit cancer cells by reversing oncogenic patterns of histone H3 lysine 4 methylation—a notion that persists to this day. This premise, however, does not withstand contemporary inspection and establishes expectations for the mechanisms and utility of WDR5 inhibitors that can likely never be met. Here, we highlight salient misconceptions regarding WDR5 inhibitors as epigenetic modulators and provide a unified model for their action as a ribosome-directed anti-cancer therapy that helps focus understanding of when and how the tumor-inhibiting properties of these agents can best be understood and exploited. |
| first_indexed | 2024-03-08T15:03:32Z |
| format | Article |
| id | doaj.art-93cd951ab6d14aadac2e1a3903c160ee |
| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-08T15:03:32Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-93cd951ab6d14aadac2e1a3903c160ee2024-01-10T15:01:54ZengMDPI AGJournal of Clinical Medicine2077-03832024-01-0113127410.3390/jcm13010274WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You ThinkApril M. Weissmiller0Stephen W. Fesik1William P. Tansey2Department of Biology, Middle Tennessee State University, Murfreesboro, TN 32132, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USADepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USAWDR5 is a conserved nuclear protein that scaffolds the assembly of epigenetic regulatory complexes and moonlights in functions ranging from recruiting MYC oncoproteins to chromatin to facilitating the integrity of mitosis. It is also a high-value target for anti-cancer therapies, with small molecule WDR5 inhibitors and degraders undergoing extensive preclinical assessment. WDR5 inhibitors were originally conceived as epigenetic modulators, proposed to inhibit cancer cells by reversing oncogenic patterns of histone H3 lysine 4 methylation—a notion that persists to this day. This premise, however, does not withstand contemporary inspection and establishes expectations for the mechanisms and utility of WDR5 inhibitors that can likely never be met. Here, we highlight salient misconceptions regarding WDR5 inhibitors as epigenetic modulators and provide a unified model for their action as a ribosome-directed anti-cancer therapy that helps focus understanding of when and how the tumor-inhibiting properties of these agents can best be understood and exploited.https://www.mdpi.com/2077-0383/13/1/274cancercancer therapyepigeneticPROTACribosomeMYC |
| spellingShingle | April M. Weissmiller Stephen W. Fesik William P. Tansey WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think Journal of Clinical Medicine cancer cancer therapy epigenetic PROTAC ribosome MYC |
| title | WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think |
| title_full | WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think |
| title_fullStr | WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think |
| title_full_unstemmed | WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think |
| title_short | WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think |
| title_sort | wd repeat domain 5 inhibitors for cancer therapy not what you think |
| topic | cancer cancer therapy epigenetic PROTAC ribosome MYC |
| url | https://www.mdpi.com/2077-0383/13/1/274 |
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