In prostate cancer, particularly in metastatic and castration-resistant forms (mCRPC), NSD2 is frequently upregulated, leading to global increases in H3K36me2. This epigenetic reprogramming alters the chromatin architecture, shifts chromatin compartmentalization, and activates oncogenic transcriptional programs which drives disease progression, metastasis, and treatment resistance.

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Emerging data highlight that elevated H3K36me2 enables transcriptional plasticity, allowing cancer cells to bypass apoptosis and resist standard-of-care therapies. Importantly, targeting NSD2 to reduce H3K36me2 levels has been shown to normalize chromatin structure, repress oncogenic gene expression, and restore treatment sensitivity in preclinical prostate cancer models.

At K36, we are advancing a potent and selective NSD2 inhibitor KTX-2001, currently in clinical development. In preclinical studies, our lead compound has demonstrated the ability to:
•    Reduce H3K36me2 levels
•    Suppress oncogenic transcriptional programs
•    Inhibit tumor cell proliferation

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These findings position NSD2 as a therapeutic target in epigenetically dysregulated, treatment-resistant prostate cancers. By disrupting the epigenetic foundation of tumor progression, our NSD2 inhibitor represents a promising new strategy for overcoming resistance and improving outcomes in patients with advanced prostate cancer.

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