Matches in SemOpenAlex for { <https://semopenalex.org/work/W3203619612> ?p ?o ?g. }
- W3203619612 abstract "Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel–Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers." @default.
- W3203619612 created "2021-10-11" @default.
- W3203619612 creator A5013040175 @default.
- W3203619612 creator A5019904868 @default.
- W3203619612 creator A5020091923 @default.
- W3203619612 creator A5026080428 @default.
- W3203619612 creator A5027842285 @default.
- W3203619612 creator A5035411478 @default.
- W3203619612 creator A5042241049 @default.
- W3203619612 creator A5043823695 @default.
- W3203619612 creator A5045578425 @default.
- W3203619612 creator A5051007979 @default.
- W3203619612 creator A5053713564 @default.
- W3203619612 creator A5054694217 @default.
- W3203619612 creator A5054811851 @default.
- W3203619612 creator A5057178272 @default.
- W3203619612 creator A5057516649 @default.
- W3203619612 creator A5070474347 @default.
- W3203619612 creator A5071843228 @default.
- W3203619612 creator A5085299627 @default.
- W3203619612 creator A5089487345 @default.
- W3203619612 date "2021-09-29" @default.
- W3203619612 modified "2023-10-12" @default.
- W3203619612 title "A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models" @default.
- W3203619612 cites W1512690422 @default.
- W3203619612 cites W1544691147 @default.
- W3203619612 cites W1755674448 @default.
- W3203619612 cites W1768917741 @default.
- W3203619612 cites W1848866248 @default.
- W3203619612 cites W1935010198 @default.
- W3203619612 cites W1965343063 @default.
- W3203619612 cites W1971948655 @default.
- W3203619612 cites W1973260880 @default.
- W3203619612 cites W1977709885 @default.
- W3203619612 cites W1982056010 @default.
- W3203619612 cites W1987170068 @default.
- W3203619612 cites W1997698058 @default.
- W3203619612 cites W1999574084 @default.
- W3203619612 cites W2002625908 @default.
- W3203619612 cites W2006593022 @default.
- W3203619612 cites W2029345540 @default.
- W3203619612 cites W2031211461 @default.
- W3203619612 cites W2033373463 @default.
- W3203619612 cites W2060309579 @default.
- W3203619612 cites W2066472373 @default.
- W3203619612 cites W2075327666 @default.
- W3203619612 cites W2087392654 @default.
- W3203619612 cites W2091983770 @default.
- W3203619612 cites W2092912586 @default.
- W3203619612 cites W2098167941 @default.
- W3203619612 cites W2099984271 @default.
- W3203619612 cites W2103441770 @default.
- W3203619612 cites W2114367386 @default.
- W3203619612 cites W2120478300 @default.
- W3203619612 cites W2126144698 @default.
- W3203619612 cites W2130410032 @default.
- W3203619612 cites W2130724559 @default.
- W3203619612 cites W2131690391 @default.
- W3203619612 cites W2144081223 @default.
- W3203619612 cites W2146501674 @default.
- W3203619612 cites W2147949826 @default.
- W3203619612 cites W2152239989 @default.
- W3203619612 cites W2163341755 @default.
- W3203619612 cites W2171808845 @default.
- W3203619612 cites W2172170481 @default.
- W3203619612 cites W2180229411 @default.
- W3203619612 cites W2292464399 @default.
- W3203619612 cites W2296606154 @default.
- W3203619612 cites W2334045973 @default.
- W3203619612 cites W2409568753 @default.
- W3203619612 cites W2422923474 @default.
- W3203619612 cites W2472017314 @default.
- W3203619612 cites W2508029612 @default.
- W3203619612 cites W2553076365 @default.
- W3203619612 cites W2553908226 @default.
- W3203619612 cites W2595529112 @default.
- W3203619612 cites W2597078857 @default.
- W3203619612 cites W2612033832 @default.
- W3203619612 cites W2621074137 @default.
- W3203619612 cites W2625583573 @default.
- W3203619612 cites W2761872853 @default.
- W3203619612 cites W2767225954 @default.
- W3203619612 cites W2790205835 @default.
- W3203619612 cites W2794383117 @default.
- W3203619612 cites W2806672448 @default.
- W3203619612 cites W2807907860 @default.
- W3203619612 cites W2810408973 @default.
- W3203619612 cites W2894309168 @default.
- W3203619612 cites W2909034820 @default.
- W3203619612 cites W2921822513 @default.
- W3203619612 cites W2948220248 @default.
- W3203619612 cites W2965339161 @default.
- W3203619612 cites W2982554531 @default.
- W3203619612 cites W2988685436 @default.
- W3203619612 cites W2989702634 @default.
- W3203619612 cites W2990781099 @default.
- W3203619612 cites W2995055858 @default.
- W3203619612 cites W2997931834 @default.
- W3203619612 cites W3013483271 @default.
- W3203619612 cites W3045203019 @default.