Targeting NSD2 to Transform Cancer Treatment
Why NSD2? A New Frontier in Epigenetic Oncology
Cancer cells increasingly exploit epigenetic mechanisms to drive malignancy, evade therapy, and promote survival, all without altering their DNA sequence. One such mechanism involves dimethylation of histone H3 at lysine 36 (H3K36me2), a key epigenetic mark associated with cancer progression. This modification is catalyzed by NSD2 (nuclear receptor-binding SET domain protein 2), a histone methyltransferase that plays a central role in chromatin remodeling and transcriptional regulation. Aberrant NSD2 activity has been linked to multiple cancers, where it drives uncontrolled cell proliferation, metastasis, and therapy resistance, making it a compelling target for next-generation cancer therapeutics.
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At K36 Therapeutics, we’re pioneering the development of selective, potent NSD2 inhibitors to treat cancers driven by epigenetic dysregulation - starting with multiple myeloma and prostate cancer.
Our Approach: Precision Inhibition of NSD2
We are advancing small molecule NSD2 inhibitors with:
• High selectivity and potency
• Favorable safety and pharmacokinetic profiles
• A biomarker-driven strategy for optimal patient selection
Our compounds are designed to block NSD2’s enzymatic activity, restoring gene expression to normal levels and slowing tumor progression. This approach offers a first-in-class opportunity in cancers with overexpression or mutation of NSD2.
In healthy tissue, the MMSET gene, located on chromosome 4, is expressed at normal levels.
The expression of the MMSET gene is regulated by a DNA element called an “enhancer”.
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MMSET activity leads to the generation of H3K36me2 marked nucleosomes, which are found on active chromatin.
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With low level activity of MMSET, there is little H3K36me2, and transcription of genes at chromatin is turned off.
There is no oncogenic activity because proper MMSET regulation and methylation produces plasma cells with normal expression of MMSET protein levels.
In t(4;14) multiple myeloma, translocation in plasma cells occurs, in which both chromosome 14 and chromosome 4 break in two. Instead of re-attaching correctly, the broken pieces of each chromosome re-attach to the other chromosome half to create two abnormal, hybrid chromosomes referred to as der(4) and der(14).
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The consequence of the t(4;14) translocation is that the MMSET gene is now placed next to a strong “enhancer” element from chromosome 14. This causes a significant increase in the transcription of MMSET, thus creating a large increase in the expression of MMSET protein.
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The increased expression of MMSET enzyme leads to an increase in H3K36me2-labeled nucleosomes. This in turn switches chromatin from being off, to being on. As a result, there is expression of cancer-promoting genes that drives the conversion of normal plasma cells into cancerous multiple myeloma cells.
KTX-1001 inhibits MMSET, which reduces the methylation and turns off the expression of genes that multiple myeloma cells need to be cancerous.
Treatment with KTX-1001 selectively treats t(4;14) multiple myeloma.
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KTX-1001 is a first-in-class highly potent inhibitor that specifically blocks the enzymatic activity of MMSET.
Treatment with KTX-1001 in t(4;14) multiple myeloma acts as a precision medicine by blocking the activity of the excessive MMSET enzyme. A decrease in H3K36me2 shuts down chromatin and turns off the expression of genes that multiple myeloma cells need to be cancerous.
