SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.
- 1Center for Cancer Research, National Cancer Institute, NIH
Abstract
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 H3K4me3, is overexpressed in ~60% of HPV-negative HNSCC tumors, it drives proliferation and invasion, and induces resistance to immunotherapy in HPV-negative HNSCC. These phenotypes are mediated partially through transcriptional regulation of cell cycle, EMT and immune-related target genes by SMYD3. Despite its enzymatic inhibitory potency in HPV-negative HNSC cell lines, the commercially available SMYD3 inhibitors EPZ031686 and BAY-6035 demonstrated no in vitro phenotypic efficacy in these cell lines, supporting that SMYD3 exerts its oncogenic functions predominantly through catalytically-independent mechanisms. Thus, to effectively target SMYD3, we designed a series of SMYD3 proteolysis targeting chimeras (PROTACs). Treatment of HPV-negative HNSCC cell lines with SMYD3 PROTACs at nanomolar concentrations degraded SMYD3 effectively and induced a drastic decrease in the proliferative and invasive potential of HPV-negative HNSCC cells. One of the designed compounds, IAP-08, showed a promising DC50 at ~177nM with Dmax of ~90%, and effectively induced the formation of ternary complexes with SMYD3 and the XIAP E3 ligase. Furthermore, IAP-08 showed a favorable pharmacokinetic profile in vivo, underscoring the feasibility for further clinical development of this compound. Mass spectrometry analysis of IAP-08 supported its high specificity towards SMYD3. SMYD3 depletion by IAP-08 in HNSCC cells revealed transcriptional regulation of cell cycle, EMT- and type I IFN response genes, in contrast to SMYD3 inhibition which had only a weak transcriptional effect. In summary, we show that inhibition of the enzymatic activity of SMYD3 is not sufficient to repress its oncogenic activity and provide evidence that depletion through PROTACs effectively targets the oncogenic functions of SMYD3 in HPV-negative HNSCC.
Related
- Vitamin D receptor is associated with farnesyl diphosphate synthase protein stability and malignant phenotypes in esophageal squamous cell carcinoma cells
- Postoperative ctDNA could potentially spare patients from unnecessary adjuvant therapy in HPV-negative head and neck squamous cell carcinoma: a meta-analysis
- Prognostic Value of Tumor Budding and Worst Pattern of Invasion in Clinically Node-Negative Early-Stage Lip and Oral Cavity Squamous Cell Carcinoma: A Systematic Review
- Transcriptomic Profiling Reveals METTL26 as a Potential Biomarker in Head and Neck Squamous Cell Carcinoma with Independent Validation in Oral Squamous Cell Carcinoma
- Clinicopathological Machine Learning Models for Mortality Risk Prediction in Head and Neck Squamous Cell Carcinoma: A Retrospective Analysis of the The Cancer Genome Atlas Head-Neck Squamous Cell Carcinoma (TCGA-HNSC) Cohort
BibTeX
@misc{saloura2026smyd3,
title = {{SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.}},
author = {V. Saloura and J. Akhtar and S. R. Doda and W. J. Moore and M. S. Dar and S. Valipour and S. Kim and J. Wu and Y. Wan and Y. Wang and M. Jiang and A. Moshiri and J. Schneekloth and S. Das and T. Andresson and R. E. Swenson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754983},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754983v1},
note = {CC0},
}
RIS
TY - UNPB
TI - SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.
AU - V. Saloura
AU - J. Akhtar
AU - S. R. Doda
AU - W. J. Moore
AU - M. S. Dar
AU - S. Valipour
AU - S. Kim
AU - J. Wu
AU - Y. Wan
AU - Y. Wang
AU - M. Jiang
AU - A. Moshiri
AU - J. Schneekloth
AU - S. Das
AU - T. Andresson
AU - R. E. Swenson
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754983
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754983v1
AB - 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 H3K4me3, is overexpressed in ~60% of HPV-negative HNSCC tumors, it drives proliferation and invasion, and induces resistance to immunotherapy in HPV-negative HNSCC. These phenotypes are mediated partially through transcriptional regulation of cell cycle, EMT and immune-related target genes by SMYD3. Despite its enzymatic inhibitory potency in HPV-negative HNSC cell lines, the commercially available SMYD3 inhibitors EPZ031686 and BAY-6035 demonstrated no in vitro phenotypic efficacy in these cell lines, supporting that SMYD3 exerts its oncogenic functions predominantly through catalytically-independent mechanisms. Thus, to effectively target SMYD3, we designed a series of SMYD3 proteolysis targeting chimeras (PROTACs). Treatment of HPV-negative HNSCC cell lines with SMYD3 PROTACs at nanomolar concentrations degraded SMYD3 effectively and induced a drastic decrease in the proliferative and invasive potential of HPV-negative HNSCC cells. One of the designed compounds, IAP-08, showed a promising DC50 at ~177nM with Dmax of ~90%, and effectively induced the formation of ternary complexes with SMYD3 and the XIAP E3 ligase. Furthermore, IAP-08 showed a favorable pharmacokinetic profile in vivo, underscoring the feasibility for further clinical development of this compound. Mass spectrometry analysis of IAP-08 supported its high specificity towards SMYD3. SMYD3 depletion by IAP-08 in HNSCC cells revealed transcriptional regulation of cell cycle, EMT- and type I IFN response genes, in contrast to SMYD3 inhibition which had only a weak transcriptional effect. In summary, we show that inhibition of the enzymatic activity of SMYD3 is not sufficient to repress its oncogenic activity and provide evidence that depletion through PROTACs effectively targets the oncogenic functions of SMYD3 in HPV-negative HNSCC.
ER -