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The Development of Chemical Tools to Target and Image Hypoxia

Vortrag (Online-Veranstaltung)

The Development of Chemical Tools to Target and Image Hypoxia

Prof. Dr. Stuart J. Conway

University of California, Los Angeles

Tumor hypoxia (low oxygen levels) is associated with resistance to all therapeutic approaches to treat cancers, and consequently poor patient prognosis. Hypoxia-activated prodrugs (HAPs), designed to selectively release a bioactive compound in oxygen-deficient cells, while sparing healthy tissue, represent a promising therapeutic strategy for treatment of cancers.[1,2] I will discuss our recent work to develop HAPs applied to a lysine deacetylase (KDAC) inhibitor and PROTACs. We have developed NI-Pano (CH-03), a novel hypoxia-activated version of the clinically approved KDAC inhibitor, panobinostat. We demonstrated the pre-clinical efficacy of NI-Pano, showing that it is stable in normoxic (21% oxygen) conditions but undergoes NADPH-CYP-mediated enzymatic bioreduction to release panobinostat selectively in hypoxia (<0.1% oxygen). Treatment of cells grown in both 2D and 3D culture with NI-Pano induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in mouse tumor xenografts. Pharmacokinetic analysis confirmed the presence of effective concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma, or kidneys.[3,4] Having demonstrated the potential of HAPs against KDACs, we sought to apply this technology to proteolysis targeting chimeras (PROTACs). PROTACs are bifunctional molecules that recruit and E3 ligase, leading to ubiquitination of a protein of interest (POI) and subsequent proteasomal degradation. By adding a bioreductive group to the E3 ligase ligand of VHL- or cereblon-recruiting PROTACs we have developed hypoxia-activated PROTACs (HAP-TACs), which selectively degrade the POI in hypoxia, but not normoxia.



References

(1) Cazares-Korner et al. ACS Chem. Biol. 2013, 8, 1451–1459.

(2) O’Connor et al. Nat. Protoc. 2016, 11, 781–794.

(3) Skwarska, Calder et al. Cell Chem. Biol. 2021, 28, 1258.

(4) Tosun, Wallabregue, Mallerman et al. JACS Au 2023, 3, 3237.

Mittwoch, 24. April 2024

15:00 – 16:00
Registration

Mittwoch, 24. April 2024

15:00 – 16:00
Registration