{
  "id": 10726947,
  "title": "SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.",
  "url": "https://urgent.news/2026/09/29/smyd3-protein-degraders-in-hpv-negative-head-and-neck-squamous-cell",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-29T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754983v1?rss=1"
  },
  "original_language": "en",
  "account": "Despite the introduction of immunotherapy in treating HPV-negative head and neck squamous cell carcinoma, the overall outlook remains unfavorable. Researchers have found that SET and MYND containing 3 (SMYD3), a protein methyltransferase, is frequently overexpressed in approximately 60% of these tumors. SMYD3 contributes to cell proliferation, invasion, and resistance to immunotherapy by regulating the expression of specific genes. Although commercially available SMYD3 inhibitors, EPZ031686 and BAY-6035, have shown no in vitro effectiveness, this suggests that SMYD3 likely influences oncogenic activities through mechanisms unrelated to its enzymatic function. To target SMYD3 more effectively, a series of protein degradation targeting chimeras (PROTACs) were developed. When tested at extremely low concentrations in HPV-negative HNSCC cell lines, these PROTACs successfully degraded SMYD3, leading to a substantial reduction in cell proliferation and invasion. One of the most promising compounds, IAP-08, achieved a DC50 of approximately 177nM and demonstrated a Dmax of around 90%. IAP-08 also formed a ternary complex with SMYD3 and the XIAP E3 ligase. Its favorable pharmacokinetic profile in vivo further supports its potential for future clinical development. Mass spectrometry confirmed IAP-08's high specificity for SMYD3. Depletion of SMYD3 using IAP-08 in HNSCC cells revealed changes in genes related to the cell cycle, EMT, and type I IFN response, indicating that SMYD3's oncogenic activity is more effectively suppressed through PROTAC-mediated depletion compared to its inhibition.",
  "summary": "Despite the advent of immunotherapy in the treatment of human-papilloma-virus (HPV)-negative head and neck squamous cell carcinoma, the overall prognosis still remains dismal. Novel therapeutic approaches are thus urgently needed. We recently reported that SET and MYND containing 3 (SMYD3), a protein methyltransferase that is known to activate the transcription of its target genes through…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}