Oral Presentation The 16th Australian Peptide Conference 2025

Targeting hGIIA-EGFR-vimentin interactions with cyclic peptide kesonotide: a novel strategy against Prostate cancer (128402)

Quach Truong 1 , Timothy J Mann 1 2 3 , Mila Sajinovic 1 2 4 , Jun Zeng 1 5 , Ramneek Kaur 1 2 , Paul De Souza 1 2 4 , Kieran F Scott 1 2 , Graham Kelly 1
  1. Filamon Limited, Sydney, New South Wales, Australia
  2. School of Medicine, Western Sydney University, Campbelltown, New South Wales, Australia
  3. School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia
  4. Nepean Clinical School, Faculty of Medicine and Health, University of Sydney, Kingswood, New South Wales, Australia
  5. MedChemSoft Solutions, Scoresby, Victoria, Australia

Prostate cancer (PCa) progression to metastatic castration-resistant prostate cancer (mCRPC) remains a significant therapeutic challenge, with limited treatment options. Increasing evidence implicates inflammation and the tumour microenvironment as critical drivers of resistance. We identified human group IIA secreted phospholipase A2 (hGIIA) as a key pro-inflammatory effector highly expressed in PCa; where it promotes tumour progression not only through its enzymatic activity but also through previously uncharacterised protein–protein interactions.

We describe kesonotide (cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg)), a novel cyclic peptide designed to inhibit hGIIA’s catalysis-independent interactions with EGFR and vimentin. In PC-3 cells, kesonotide blocks hGIIA-driven EGFR phosphorylation (p = 0.0016), downstream pERK (p = 0.0039) and cPLA2-α signalling (p = 0.0478), suppresses prostaglandin E₂ (PGE₂) production (p = 0.0065), and induces vimentin-mediated aggresome formation and apoptosis in vitro (p < 0.0001). Notably, the IC₅₀ for kesonotide inhibition of the hGIIA–vimentin interaction was 56.5 µM.

Kesonotide demonstrated potent anti-tumour activity in vivo, reducing tumour volume significantly in xenografts of early stage (p<0.05) and late stage PCa (p<0.001) —at doses as low as 0.1 mg/kg orally. Survival benefits were marked for late stage PCa: 27% of animals treated with kesonotide survived the 6-month study, which is higher than the response rate for docetaxel (12%), the current standard of care for men with castrate-resistant PCa. Tumour regression or stasis was observed in all long-term survivors. Kesonotide showed excellent safety in mice and rats, with no observable toxicity in 28-day OECD-compliant studies, and demonstrated 10% oral bioavailability and strong cell permeability.

These findings establish kesonotide as a lead compound targeting non-catalytic functions of hGIIA and support its clinical development. Given that hGIIA, EGFR, and vimentin are overexpressed in other malignancies, this mechanism may have broader oncologic relevance beyond prostate cancer.