Main content area

Identification of LEM-14 inhibitor of the oncoprotein NSD2

Shen, Yunpeng, Morishita, Masayo, Lee, Doohyun, Kim, Shinae, Lee, Taeho, Mevius, Damiaan E.H.F., Roh, Yeonjeong, di Luccio, Eric
Biochemical and biophysical research communications 2019 v.508 no.1 pp. 102-108
chromatin, drugs, histones, inhibitory concentration 50, lysine, methyltransferases, myeloma, non-Hodgkin lymphoma, oncogene proteins, prognosis, therapeutics
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.