2. Academic Validation
  3. Dyr726, a brain-penetrant inhibitor of PI3Kα, Type III receptor tyrosine kinases, and WNT signaling

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

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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