Targeting the Nuclear Receptor-Binding SET Domain Family of Histone Lysine Methyltransferases for Cancer Therapy: Recent Progress and Perspectives

Abstract

Nuclear receptor-binding SET domain (NSD) proteins are a class of histone lysine methyltransferases (HKMTases) that are amplified, mutated, translocated, or overexpressed in various types of cancers. Several campaigns to develop NSD inhibitors for cancer treatment have begun following recent advances in knowledge of NSD1, NSD2, and NSD3 structures and functions as well as the U.S. FDA approval of the first HKMTase inhibitor (tazemetostat, an EZH2 inhibitor) to treat follicular lymphoma and epithelioid sarcoma. This perspective highlights recent findings on the structures of catalytic su(var), enhancer-of-zeste, trithorax (SET) domains and other functional domains of NSD methyltransferases. In addition, recent progress and efforts to discover NSD-specific small molecule inhibitors against cancer-targeting catalytic SET domains, plant homeodomains, and proline-tryptophan-tryptophan-proline domains are summarized.

Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors

“…To evaluate whether the inhibition of EZH2 by 15a contributes to its cellular activity on KMS-11 cells, we performed antiproliferative activity of EPZ6438, 6 a potent EZH2 inhibitor in the same KMS-11 cells. As shown in Table 7, EPZ6438 exhibited potent inhibitory activity against EZH2, with an IC 50 value of 0.022 μM.…”

“…As an important class of epigenetic modifiers, histone lysine methyltransferase nuclear receptor-binding SET domain (NSD) proteins utilize S -adenosyl- L -methionine (SAM) as the methyl donor to catalyze the monomethylation and dimethylation of the ε-amino moiety of lysine 36 of histone H3 (H3K36), an important process closely involved in the gene transcription, DNA replication, and cellular differentiation. − The NSD family is categorized into NSD1, NSD2, and NSD3, which all are multidomain proteins, mainly including the catalytic SET domain, PWWP domain, and PHD finger . NSD2, the primary enzyme responsible for H3K36 dimethylation, is overexpressed, translocated, or mutated in multiple types of hematological malignancies and solid tumors. , Notably, the t(4; 14) (p16; q32) translocation, observed in approximately 20% of multiple myeloma (MM) cases, leads to the overexpression of both NSD2 and FGFR3, with NSD2 considered to be the predominant oncogenic driver. − In addition, the hyperactivation of NSD2 E1099K mutation was identified in multiple acute lymphoblastic leukemia (ALL) cell lines. , Both E1099K mutation and overexpression of NSD2 result in a global elevation of H3K36me2 levels and drive tumorigenesis and oncogenic transformation, whereas knockdown of NSD2 was found to inhibit cancer cell tumorigenesis and proliferation. , Therefore, pharmacological inhibition of NSD2 with small molecules has emerged as a promising strategy for the treatment of cancers involving dysfunction of NSD2.…”

“…The catalytic SET domain plays a crucial role in NSD2 activity. Therefore, targeting the SET domain with small molecules could be an effective strategy for the development of NSD2 inhibitors. , By using a quantitative high-throughput screening platform, Hall and co-workers screened over 16,000 bioactive compounds and identified five synthetic small molecule inhibitors targeting NSD2 catalytic SET domain . Among them, DA3003-1 ( 6 , Figure ) was found to exhibit the most potent inhibitory activity with an IC 50 value of 0.17 μM and inhibited NSD2 activity in human osteosarcoma (U2OS) cells.…”

“…4 NSD2, the primary enzyme responsible for H3K36 dimethylation, is overexpressed, translocated, or mutated in multiple types of hematological malignancies and solid tumors. 5,6 Notably, the t(4; 14) (p16; q32) translocation, observed in approximately 20% of multiple myeloma (MM) cases, leads to the overexpression of both NSD2 and FGFR3, with NSD2 considered to be the predominant oncogenic driver. 7−9 In addition, the hyperactivation of NSD2 E1099K mutation was identified in multiple acute lymphoblastic leukemia (ALL) cell lines.…”

“…The PWWP domain is essential for NSD2 to bind and methylate histone H3 and DNA. , On this basis, Li and co-workers reported a potent NSD2 inhibitor 8 binding to PWWP1 domain with an IC 50 value of 0.11 μM. This compound can affect the expression of genes regulated by NSD2 and might be used as a chemical probe to define NSD2 biology .…”