TY - JOUR
T1 - Inhibition of USP10 induces degradation of oncogenic FLT3
AU - Weisberg, Ellen L.
AU - Schauer, Nathan J.
AU - Yang, Jing
AU - Lamberto, Ilaria
AU - Doherty, Laura
AU - Bhatt, Shruti
AU - Nonami, Atsushi
AU - Meng, Chengcheng
AU - Letai, Anthony
AU - Wright, Renee
AU - Tiv, Hong
AU - Gokhale, Prafulla C.
AU - Ritorto, Maria Stella
AU - De Cesare, Virginia
AU - Trost, Matthias
AU - Christodoulou, Alexandra
AU - Christie, Amanda
AU - Weinstock, David M.
AU - Adamia, Sophia
AU - Stone, Richard
AU - Chauhan, Dharminder
AU - Anderson, Kenneth C.
AU - Seo, Hyuk Soo
AU - Dhe-Paganon, Sirano
AU - Sattler, Martin
AU - Gray, Nathanael S.
AU - Griffin, James D.
AU - Buhrlage, Sara J.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
AB - Oncogenic forms of the kinase FLT3 are important therapeutic targets in acute myeloid leukemia (AML); however, clinical responses to small-molecule kinase inhibitors are short-lived as a result of the rapid emergence of resistance due to point mutations or compensatory increases in FLT3 expression. We sought to develop a complementary pharmacological approach whereby proteasome-mediated FLT3 degradation could be promoted by inhibitors of the deubiquitinating enzymes (DUBs) responsible for cleaving ubiquitin from FLT3. Because the relevant DUBs for FLT3 are not known, we assembled a focused library of most reported small-molecule DUB inhibitors and carried out a cellular phenotypic screen to identify compounds that could induce the degradation of oncogenic FLT3. Subsequent target deconvolution efforts allowed us to identify USP10 as the critical DUB required to stabilize FLT3. Targeting of USP10 showed efficacy in preclinical models of mutant-FLT3 AML, including cell lines, primary patient specimens and mouse models of oncogenic-FLT3-driven leukemia.
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U2 - 10.1038/nchembio.2486
DO - 10.1038/nchembio.2486
M3 - Article
C2 - 28967922
AN - SCOPUS:85034845782
VL - 13
SP - 1207
EP - 1215
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
IS - 12
ER -