Identification of a potent and noncytotoxic inhibitor of melanin production

On the basis of a hit from random screening, biaryl amide derivatives were prepared in a combinatorial manner via parallel solution-phase synthesis, and their effects on melanocytes were investigated to discover new effective skin depigmenting agents. Among the 120 derivatives prepared, five members exhibited a >30% reduction of melanin production at 30 μM with a cell viability of >90%. In particular, compound A₃/B₅ exhibited effective inhibitory activity on melanin synthesis. Although the inhibition percentage of A₃/B₅ was slightly lower than that of the positive reference compound, phenylthiourea (PTU), A₃/B₅ demonstrated a much better cell viability than PTU. In vivo evaluation of A₃/B₅ also showed a significant decrease of melanin pigments. In addition, the in silico classification model was built based on the experimental data of library members. Our results suggest that these biaryl amide derivatives may act as potent skin depigmenting agents.     

Identification of LEM-14 inhibitor of the oncoprotein NSD2

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.