TY - JOUR
T1 - Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos
AU - Meng, Fanye
AU - Xu, Chenxi
AU - Park, Kwang Su
AU - Kaniskan, H. Ümit
AU - Wang, Gang Greg
AU - Jin, Jian
N1 - Funding Information:
This work was supported in part by the U.S. National Institutes of Health grants R01GM122749 (to J.J.), P30CA196521 (to J.J.), R01CA211336 (to G.G.W.), R01CA215284 (to G.G.W), 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. We thank Drs. Minkui Luo, Deyao Li, and Ke Wang for their generous help with obtaining HRMS results at the MSKCC Analytical Core Facility. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/8/11
Y1 - 2022/8/11
N2 - Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9 (MS159), and two structurally similar controls, 17 (MS159N1) and 18 (MS159N2), with diminished binding to the cereblon (CRBN) E3 ligase and NSD2, respectively. Compound 9, but not 17 and 18, effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner. Compound 9 also effectively degraded CRBN neo-substrates IKZF1 and IKZF3, but not GSPT1. Importantly, compound 9 was much more effective in suppressing the growth in cancer cells than the parent NSD2 binder. Moreover, compound 9 was bioavailable in mice. Altogether, compound 9 and its two controls 17 and 18 are valuable chemical tools for exploring the roles of NSD2 in health and disease.
AB - Overexpression of nuclear receptor binding SET domain protein 2 (NSD2) is frequent in multiple myeloma (MM). However, existing NSD2 inhibitors are largely ineffective in suppressing MM cell proliferation. Here, we report the discovery of a first-in-class NSD2 proteolysis targeting chimera (PROTAC) degrader, 9 (MS159), and two structurally similar controls, 17 (MS159N1) and 18 (MS159N2), with diminished binding to the cereblon (CRBN) E3 ligase and NSD2, respectively. Compound 9, but not 17 and 18, effectively degraded NSD2 in a concentration-, time-, CRBN-, and proteasome-dependent manner. Compound 9 also effectively degraded CRBN neo-substrates IKZF1 and IKZF3, but not GSPT1. Importantly, compound 9 was much more effective in suppressing the growth in cancer cells than the parent NSD2 binder. Moreover, compound 9 was bioavailable in mice. Altogether, compound 9 and its two controls 17 and 18 are valuable chemical tools for exploring the roles of NSD2 in health and disease.
UR - http://www.scopus.com/inward/record.url?scp=85136144053&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c00807
DO - 10.1021/acs.jmedchem.2c00807
M3 - Article
C2 - 35895319
AN - SCOPUS:85136144053
SN - 0022-2623
VL - 65
SP - 10611
EP - 10625
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -