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Identification of LEM-14 inhibitor of the oncoprotein NSD2

Author:
Shen, Yunpeng, Morishita, Masayo, Lee, Doohyun, Kim, Shinae, Lee, Taeho, Mevius, Damiaan E.H.F., Roh, Yeonjeong, di Luccio, Eric
Source:
Biochemical and biophysical research communications 2019 v.508 no.1 pp. 102-108
ISSN:
0006-291X
Subject:
chromatin, drugs, histones, inhibitory concentration 50, lysine, methyltransferases, myeloma, non-Hodgkin lymphoma, oncogene proteins, prognosis, therapeutics
Abstract:
The NSD family (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1) are histone lysine methyltransferases (HMTases) essential for chromatin regulation. The NSDs are oncoproteins, drivers of a number of tumors and are considered important drug-targets but the lack of potent and selective inhibitors hampers further therapeutic development and limits exploration of their biology. In particular, MMSET/NSD2 selective inhibition is being pursued for therapeutic interventions against multiple myeloma (MM) cases, especially in multiple myeloma t(4;14)(p16.3;q32) translocation that is associated with a significantly worse prognosis than other MM subgroups. Multiple myeloma is the second most common hematological malignancy, after non-Hodgkin lymphoma and remains an incurable malignancy.Here we report the discovery of LEM-14, an NSD2 specific inhibitor with an in vitro IC50 of 132 μM and that is inactive against the closely related NSD1 and NSD3. LEM-14-1189, a LEM-14 derivative, differentially inhibits the NSDs with in vitro IC50 of 418 μM (NSD1), IC50 of 111 μM (NSD2) and IC50 of 60 μM (NSD3). We propose LEM-14 and derivative LEM-14-1189 as tools for studying the biology of the NSDs and constitute meaningful steps toward potent NSDs therapeutic inhibitors.
Agid:
6225485