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 IC 50 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 IC 50 of 418 μM (NSD1), IC 50 of 111 μM (NSD2) and IC 50 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. Highlights • NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 are histone methyltransferases and oncoproteins. • Inhibition of NSD2 in multiple myeloma t(4;14)(p16.3;q32) is urgently needed. • We report the discovery of a NSD2 specific inhibitor and derivatives that differentially inhibits the NSDs. • We investigate the molecular mechanism for NSD2 specific inhibition. • We propose our inhibitors LEM-14 and LEM-14-1189 as tools for studying the biology of the NSDs and for drug-design. [ABSTRACT FROM AUTHOR]