CLK2 inhibitors(CDC like kinase 2 inhibitors), DYRK inhibitors(DYRK kinase inhibitors), PDGFR antagonists(Platelet-derived growth factor receptor antagonists)

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Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

Glioblastoma Multiforme

Inactive Indication-

Originator Organization

University of Arizona

Active Organization

University of Arizona

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with DYR-726

100 Translational Medicine associated with DYR-726

100 Patents (Medical) associated with DYR-726

Literatures (Medical) associated with DYR-726

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

Article

Author: Wilms, Gerrit ; Banerjee, Sourav ; Miller, Amy Dunne ; Ellis, Nathan ; Gokhale, Vijay ; Montfort, William ; Bedard, Nathan ; Elliott, Richard ; Atmasidha, Aditi ; Prescott, Alan R ; Cabel, Carly ; Ginn, Sean ; Yagel, Mary ; Masson, Glenn R ; Thorne, Curtis ; Rahman, Ruman ; Sharma, Ira ; Hulme, Christopher ; Rokey, Samantha N ; Tandon, Vasudha ; Duncan, Christina ; Chavez, Timothy ; Nogales, Joaquina ; McMahon, Aidan ; Basantes, L Emilia ; Carragher, Neil ; Smith, Stuart J ; Fistrovich, Alessandra ; Shaw, Yeng ; Becker, Walter ; Chalmers, Anthony J ; Read, Kevin D ; Williams, Karin ; Ferro, Febe

AbstractThe 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. Usingde novosynthesis 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 within vitro,in vivoefficacy, 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.

100 Deals associated with DYR-726

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Preclinical	-	University of Arizona	-

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