Dyr726, a brain-penetrant inhibitor of PI3Kα, Type III receptor tyrosine kinases, and WNT signaling

  • bioRxiv. 2025 Mar 29:2025.03.26.645490. doi: 10.1101/2025.03.26.645490.
Vasudha Tandon  1 ,  Alessandra Fistrovich  2  3 ,  Joaquina Nogales  1 ,  Febe Ferro  1 ,  Samantha N Rokey  2  3 ,  Carly Cabel  4 ,  Amy Dunne Miller  1 ,  Mary Yagel  4 ,  Christina Duncan  5 ,  Aditi Atmasidha  1 ,  Ira Sharma  1 ,  Gerrit Wilms  6 ,  Karin Williams  7 ,  Richard Elliott  8 ,  Timothy Chavez  2 ,  Yeng Shaw  2 ,  Aidan McMahon  2 ,  Sean Ginn  2 ,  L Emilia Basantes  2 ,  Nathan Bedard  2 ,  Vijay Gokhale  3 ,  Nathan Ellis  4 ,  Alan R Prescott  9 ,  Stuart J Smith  10 ,  Ruman Rahman  10 ,  Walter Becker  6 ,  Kevin D Read  5 ,  Anthony J Chalmers  7 ,  Neil Carragher  8 ,  Glenn R Masson  1 ,  William Montfort  2 ,  Curtis Thorne  4 ,  Christopher Hulme  2  3 ,  Sourav Banerjee  1
Affiliations
  • 1. Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, UK.
  • 2. Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA.
  • 3. Division of Drug Discovery Development, Department of Pharmacology & Toxicology, The College of Pharmacy, The University of Arizona, Tucson, AZ, 85721, USA.
  • 4. University of Arizona Cancer Center, Department of Cellular and Molecular Medicine, College of Medicine, The University of Arizona, Tucson, AZ, USA.
  • 5. Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
  • 6. Institute of Pharmacology and Toxicology, RWTH Aachen University, 52074 Aachen, Germany.
  • 7. School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
  • 8. The Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK.
  • 9. Dundee Imaging Facility, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
  • 10. Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK.
PMID: 40196701 DOI: 10.1101/2025.03.26.645490
Abstract

The vast majority of clinical small molecule multi-kinase inhibitors (mKI) report abject failures in targeting cancers with high stem cell contents like high-grade glioma and colorectal cancers. The FDA-approved mKIs to date ablate receptor tyrosine kinase signaling but do not target the paradoxical Wnt signaling which is a key survival driver for the self-renewing Cancer Stem Cells. The Wnt pathway enhances Cancer plasticity and triggers relapse of highly heterogenous tumours. Using de novo synthesis and structure-activity-relationship (SAR) studies with blood-brain-barrier (BBB) penetrant mKI scaffolds, we designed a highly potent and selective small molecule inhibitor of PI3Kα, PDGFR/KIT, and the Wnt pathway denoted Dyr726. Dyr726 is superior to clinical mKIs and inhibits PI3K-AKT-mTOR and WNT-pathway signaling at multiple nodes thereby impeding proliferation, invasion, and tumour growth. Phospho-proteomic, structural, and target engagement analyses, combined with in vitro, in vivo efficacy, and pharmacokinetic studies reveal that Dyr726 is a brain-penetrant small molecule which effectively reduces tumour volume and extends survival of murine orthotopic models. Our current work establishes a first-in-class brain penetrant small molecule mKI which simultaneously antagonize the PI3K-AKT-mTOR and Wnt pathways in preclinical Cancer stem cell cultures, adult and pediatric primary organoids, and orthotopic murine models with positive efficacy in combination with clinical standard of care.

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