@article{9fd89317271e4aa78649f0fe514ac256,
title = "A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells",
abstract = "Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated oncogenic actions are currently lacking. We report the NSD3-targeting proteolysis targeting chimera (PROTAC), MS9715, which achieves effective and specific targeting of NSD3 and associated cMyc node in tumor cells. MS9715 is designed by linking BI-9321, a NSD3 antagonist, which binds NSD3{\textquoteright}s PWWP1 domain, with an E3 ligase VHL ligand. Importantly, MS9715, but not BI-9321, effectively suppresses growth of NSD3-dependent hematological cancer cells. Transcriptomic profiling demonstrates that MS9715, but not BI-9321, effectively suppresses NSD3-and cMyc-associated gene expression programs, resembling effects of the CRISPR-Cas9-mediated knockout of NSD3. Collectively, these results suggest that pharmacological degradation of NSD3 as an attractive therapeutic strategy, which co-suppresses NSD3- and cMyc-related oncogenic nodes, is superior to blocking the PWWP1 domain of NSD3.",
keywords = "NSD3, PROTAC, cMyc, cancer, chromatin, degrader, epigenetics, histone, ubiquitylation",
author = "Chenxi Xu and Fanye Meng and Park, {Kwang Su} and Storey, {Aaron J.} and Weida Gong and Tsai, {Yi Hsuan} and Elisa Gibson and Byrum, {Stephanie D.} and Dongxu Li and Edmondson, {Rick D.} and Mackintosh, {Samuel G.} and Masoud Vedadi and Ling Cai and Tackett, {Alan J.} and Kaniskan, {H. {\"U}mit} and Jian Jin and Wang, {Gang Greg}",
note = "Funding Information: This work was supported in part by the US National Institutes of Health grants R01GM122749 (to J.J.), P30CA196521 (to J.J.), R01CA211336 (to G.G.W.), R01CA215284 (to G.G.W), R24GM137786 (to A.J.T.), P20GM121293 (to A.J.T.), R01CA236209 (to A.J.T.), P20GM103429 (to A.J.T.), and an NIH/Office of the Director Grant S10OD018445 (to S.G.M.), an endowed professorship from the Icahn School of Medicine at Mount Sinai (to J.J.), and grants/awards from Gabrielle's Angel Foundation for Cancer Research (to G.G.W.), When Everyone Survives (WES) Leukemia Research Foundation (to G.G.W.) and UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants (to G.G.W. and L.C.). G.G.W. is an American Cancer Society (ACS) Research Scholar, a Leukemia and Lymphoma Society (LLS) Scholar, and an American Society of Hematology (ASH) Scholar in Basic Science. This work utilized the AVANCE NEO 600 MHz NMR Spectrometer System that was upgraded with funding from a National Institutes of Health SIG grant 1S10OD025132-01A1. We thank UNC's facilities, including High-throughput Sequencing Facility (HTSF), Bioinformatics Core, and Flow Cytometry Core, for their professional assistance of this work. The cores affiliated to the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30CA016086. C.X. and F.M. performed biological studies and chemical synthesis and characterization, respectively. K.-S.P. conducted biophysical characterization. A.J.S. S.G.M. R.D.E. and S.D.B. performed mass spectrometry-based proteomics analyses under the supervision of A.J.T. W.G. Y.-H.T. C.X. L.C. and G.G.W. conducted omics data analysis. E.G. and M.V. expressed and purified the NSD3 protein. D.L. created cell lines used in the work. C.X. F.M. K.-S.P. L.C. H.Ṻ.K. J.J. and G.G.W. interpreted the data. G.G.W. J.J. and H.Ṻ.K. conceived the project, and organized and led the study. C.X. F.M. H.Ṻ.K. J.J. and G.G.W. wrote the manuscript with input from other authors. The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, and Cullgen, Inc. The Wang laboratory received research funds from the Deerfield Management/Pinnacle Hill Company. J.J. is an equity shareholder and consultant of Cullgen, Inc. Funding Information: This work was supported in part by the US National Institutes of Health grants R01GM122749 (to J.J.), P30CA196521 (to J.J.), R01CA211336 (to G.G.W.), R01CA215284 (to G.G.W), R24GM137786 (to A.J.T.), P20GM121293 (to A.J.T.), R01CA236209 (to A.J.T.), P20GM103429 (to A.J.T.), and an NIH /Office of the Director Grant S10OD018445 (to S.G.M.), an endowed professorship from the Icahn School of Medicine at Mount Sinai (to J.J.), and grants/awards from Gabrielle's Angel Foundation for Cancer Research (to G.G.W.), When Everyone Survives (WES) Leukemia Research Foundation (to G.G.W.) and UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants (to G.G.W. and L.C.). G.G.W. is an American Cancer Society (ACS) Research Scholar, a Leukemia and Lymphoma Society (LLS) Scholar, and an American Society of Hematology (ASH) Scholar in Basic Science. This work utilized the AVANCE NEO 600 MHz NMR Spectrometer System that was upgraded with funding from a National Institutes of Health SIG grant 1S10OD025132-01A1 . We thank UNC's facilities, including High-throughput Sequencing Facility (HTSF), Bioinformatics Core, and Flow Cytometry Core, for their professional assistance of this work. The cores affiliated to the UNC Cancer Center are supported in part by the UNC Lineberger Comprehensive Cancer Center Core Support Grant P30CA016086 . Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2022",
month = mar,
day = "17",
doi = "10.1016/j.chembiol.2021.08.004",
language = "English",
volume = "29",
pages = "386--397.e9",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "3",
}