Epigenetic abnormalities are very common in human cancers and play a critical role in tumorigenesis via
dysregulation of gene expression and by affecting chromatin function. Inhibition of enzymes involved in
epigenetic modifications has been recognized as a very attractive approach to develop novel drugs. Histone
methyltransferases (HMTs) emerged as very promising class of anti-cancer drug targets and several recently
developed inhibitors have been advanced to clinical trials, including inhibitors of DOT1L, EZH2 and PRMT5.
These examples clearly emphasize significance of developing HMT inhibitors as novel anti-cancer drugs.
In this project we propose to develop inhibitors of NSD1 histone methyltransferase. Translocation of NSD1
gene with Nup98 leading to Nup98-NSD1 fusion protein is found in pediatric acute myeloid leukemia patients
with very poor prognosis. It has been validated that histone-methyltrasferase activity of NSD1 SET domain is
required for oncogenic activity of Nup98-NSD1. To date, no NSD1 inhibitors have been described. We have
identified small molecule compounds binding to NSD1 SET domain and employed extensive medicinal
chemistry to significantly improve their activity. We developed potent cell-active NSD1 inhibitors blocking
proliferation of Nup98-NSD1 cells. For our lead compound, we also demonstrated efficacy in animal model of
Nup98-NSD1 leukemia. In this proposal, we will develop and optimize two classes of NSD1 inhibitors with two
different mechanisms of action. We will optimize potency and drug-like properties of NSD1 inhibitors and
perform extensive efficacy studies in animal models. In addition, our goal is to develop patient-derived
xenograft (PDX) model of Nup98-NSD1 leukemia for efficacy studies. Our project will result in potent drug-like
NSD1 inhibitors to be used as chemical probes and novel pharmacologic agents for acute leukemia.