My lab along other groups have previously emphasized the role of NSD proteins (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1)  as oncogenes. A growing number of studies link the NSD proteins to a variety of cancers. NSD1 is associated with acute myeloid leukemia, multiple myeloma, and lung cancer; NSD2 with the prostate cancer and multiple myeloma; NSD3 with both lung and breasts cancers along with the acute myeloid leukemia. NSD1-NUP98 translocation is associated with childhood acute myeloid leukemia with the NUP98-NSD1 fusion protein being an active H3K36 methylase. NSD1 is amplified in multiple myeloma, lung cancer, neuroblastomas and glioblastomas NSD2 has been found associated with the prostate cancer and multiple myeloma. Furthermore, the amplification of either NSD1 or NSD2 trigger the cellular transformation, initiating carcinogenesis events . Increased NSD2 activity was reported in the tumor proliferation in glioblastoma multiforms. Overexpression of NSD2 in myeloma cells leads to aberrantly high global levels of H3K36 di-methylation, accompanied by a decrease in levels of H3K27 methylation. In myeloma cells, NSD2 contributes to disrupt the chromatin structure and function contributing to the cellular transformation. In addition, NSD2 is found overexpressed in 15 different cancers and is associated with tumor aggressiveness or prognosis in most types of cancers. NSD3 is found amplified in breast cancer cell lines and primary breast carcinomas. Moreover, NSD3 is involved in lung cancer and the acute myeloid leukemia where NSD3 is fused with NUP98, similarly as NSD1.

Reducing NSDs activity through specific lysine-HMTase inhibitors appears promising to help suppressing cancer growth.

Over the last few months, we have been doing extensive virtually ligand screening of thousands of selected compounds along with a large number of HMTase assays. Here a short video of the top 10 molecules that tightly bind (inhibit) the histone lysine binding pocket of the SET domain of NSD2/MMSET/WHSC1, calculated in an “open-conformation (able to dock the histone lysine H3K36).