Recent advances in nuclear receptor-binding SET domain 2 (NSD2) inhibitors: An update and perspectives

Zhang, Li; Zha, Xiaoming

doi:10.1016/j.ejmech.2023.115232

Cited by 10 publications

(9 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we mentioned earlier, NSD2 is a promising therapeutic target, and its translocation, mutations, and overexpression are closely associated with the proliferation, migration, and invasion of cancer cells. ,− However, developing small-molecule inhibitors targeting the catalytic SET domain has yielded little success. , Recently, a selective covalent NSD1 inhibitor 30 (BT5) and two specific NSD2 inhibitors 11 (LEM-14) and KTX-1001 ( Identifier: NCT05651932) that target the catalytic SET domain have been identified. , Among previously reported NSD inhibitors, 30 (BT5) and 11 (LEM-14) are the first inhibitors selectively targeting NSD1 and NSD2, respectively. Other than the catalytic SET domain, NSD2 also possesses multiple PPI domains, including PHD domains and PWWP domains (PWWP1 and PWWP2), , which may be clinically relevant and selectively blocked by small molecules (Figure ).…”

Section: Targeting Nsd2 As a Potential Therapeutic Strategy For Cance...mentioning

confidence: 99%

“…11,21−23 NSD2 has been identified as a promising drug target, receiving more and more attention from both academia and the pharmaceutical industry. 24,25 Therefore, developing potent and selective small-molecule NSD2 inhibitors may provide potential novel therapies for patients carrying NSD2 overexpression, translocation, and/or mutation. Such compounds may also serve as useful pharmacological tools for exploring the critical roles of NSD2 in various human diseases.…”

Section: ■ Introductionmentioning

confidence: 99%

“…To date, several smallmolecule NSD2 inhibitors and degraders have been reported, targeting either the catalytic SET domain or the prolinetryptophan-tryptophan-proline (PWWP) domain with representative chemical structures shown in Figure 3. 24,25 However, these inhibitors mainly target the catalytic SET domain, having little success likely owing to poor enzymatic and/or cellular potency, as well as the subtype selectivity, etc. Discovery and development of more potent and specific NSD2 inhibitors are urgently needed.…”

Section: ■ Introductionmentioning

confidence: 99%

“…NSD2 is aberrantly overexpressed, amplified, or somatically mutated in multiple types of cancer and has been defined as an oncoprotein. − Notably, NSD2 is overexpressed in multiple myeloma (MM) patients, predominantly harboring a t(4,14) translocation that leads to the aberrant upregulation of this gene. − A recurrent gain-of-function mutation with the substitution of glutamic acid to lysine at residue 1099 (p.Glu1099Lys, p.E1099K) in the catalytic SET domain of NSD2 has been revealed in pediatric acute lymphoblastic leukemia (ALL) patients. NSD2 p.E1099K hyperactivates its methyltransferase activity, driving oncogenesis and progression. − Accumulating evidence indicates that NSD2 is overexpressed in various cancers such as MM, skin, lung, bladder, brain, metaplastic breast, and prostate cancer (PCa). ,− NSD2 has been identified as a promising drug target, receiving more and more attention from both academia and the pharmaceutical industry. , Therefore, developing potent and selective small-molecule NSD2 inhibitors may provide potential novel therapies for patients carrying NSD2 overexpression, translocation, and/or mutation. Such compounds may also serve as useful pharmacological tools for exploring the critical roles of NSD2 in various human diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Given the driving roles of NSD2 in various diseases and simultaneously inspired by the great success in devolving selective potent EZH2 and DOT1L inhibitors, as well as other HKMTases inhibitors, substantial efforts have been made to identify potent NSD2 inhibitors. To date, several small-molecule NSD2 inhibitors and degraders have been reported, targeting either the catalytic SET domain or the proline-tryptophan-tryptophan-proline (PWWP) domain with representative chemical structures shown in Figure . , However, these inhibitors mainly target the catalytic SET domain, having little success likely owing to poor enzymatic and/or cellular potency, as well as the subtype selectivity, etc. Discovery and development of more potent and specific NSD2 inhibitors are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

Bolinger

Chen

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Nuclear receptor binding SET domain proteins (NSDs) catalyze the mono-or dimethylation of histone 3 lysine 36 (H3K36me1 and H3K36me2), using S-adenosyl-L-methionine (SAM) as a methyl donor. As a key member of the NSD family of proteins, NSD2 plays an important role in the pathogenesis and progression of various diseases such as cancers, inflammations, and infectious diseases, serving as a promising drug target. Developing potent and specific NSD2 inhibitors may provide potential novel therapeutics. Several NSD2 inhibitors and degraders have been discovered while remaining in the early stage of drug development. Excitingly, KTX-1001, a selective NSD2 inhibitor, has entered clinical trials. In this Perspective, the structures and functions of NSD2, its roles in various human diseases, and the recent advances in drug discovery strategies targeting NSD2 have been summarized. The challenges, opportunities, and future directions for developing NSD2 inhibitors and degraders are also discussed. ■ SIGNIFICANCE• Small-molecule NSD2 inhibitors and degraders show therapeutic promise for NSD2-driven and -associated diseases, especially cancers. • The recent advances in drug discovery efforts targeting NSD2 are systematically summarized. • Current challenges and opportunities as well as future directions for developing NSD2 inhibitors and degraders are discussed from the medicinal chemistry perspective. • This Perspective provides insights into future drug discovery strategies targeting NSD2.

show abstract

Section: Targeting Nsd2 As a Potential Therapeutic Strategy For Cance...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Drug Discovery Targeting Nuclear Receptor Binding SET Domain Protein 2 (NSD2)

Bolinger

Chen

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

Proteomics contributions to epigenetic drug discovery

Noberini,

Bonaldi

2023

Proteomics

View full text Add to dashboard Cite

The combined activity of epigenetic features, which include histone post‐translational modifications, DNA methylation, and nucleosome positioning, regulates gene expression independently from changes in the DNA sequence, defining how the shared genetic information of an organism is used to generate different cell phenotypes. Alterations in epigenetic processes have been linked with a multitude of diseases, including cancer, fueling interest in the discovery of drugs targeting the proteins responsible for writing, erasing, or reading histone and DNA modifications. Mass spectrometry (MS)‐based proteomics has emerged as a versatile tool that can assist drug discovery pipelines from target validation, through target deconvolution, to monitoring drug efficacy in vivo. Here, we provide an overview of the contributions of MS‐based proteomics to epigenetic drug discovery, describing the main approaches that can be used to support different drug discovery pipelines and highlighting how they contributed to the development and characterization of epigenetic drugs.

show abstract