Abstract 4517: Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC)

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite advances in treatments and significant efficacy of immunotherapy drugs in HNSCC, no effective targeted therapies have been approved in this disease yet. NSD2 is a histone lysine methyltransferase, which is overexpressed in HNSCC and is implicated in tumor growth, cell cycle regulation, epithelial-mesenchymal transition (EMT) and metastasis not only in HNSCC, but also in many other solid tumors. Development of inhibitors to the catalytic activity of NSD2 has been rather limited to date, which necessitates an alternative approach. To target NSD2, we have recently developed a series of novel proteolysis targeting chimeras (PROTACs), which chemically degrade NSD2 utilizing native cellular machinery - ubiquitin-proteasome system - with VHL as an E3 ligase. A series of >40 compounds were tested in HNSCC cell lines (JHU-011 and FaDu) and NSD2-dependent multiple myeloma cell line (KMS11) for degradation activity against NSD2 protein, and H3K36me2 chromatin mark reduction, using Western blot. We also tested their anti-proliferative activity in cell viability assay (CTB) and clonogenic assay. Compounds NUCC-0227381, NUCC-0227384, NUCC-0227414 and NUCC-0227383 show promising results by reducing NSD2 and H3K36me2 levels. NUCC-0227383 compound was highly promising, as it was the most potent in reducing NSD2/K36me2 levels without affecting NSD1/NSD3 levels and had profound effects on HNSCC cell growth. Lead compound NUCC-0227383 was chosen for further testing and in preliminary testing, showed a dose-dependent, VHL-mediated, and proteasome dependent function. Proteomics analysis, testing for specificity of NUCC-0227383 against a panel of histone methyltransferases, and in vivo testing of this promising compound against HNSCC is planned. Citation Format: Amr Ismail, Ekaterina Roshchina, Iuliia Topchu, Gary Schiltz, Yanis Boumber. Novel chemical degraders targeting NSD2 in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4517.