ESPE2022 Free Communications Early Life and Multisystem Endocrinology (6 abstracts)
Evaluating the Utility of Bi-functional Degrader Molecules for Selective Inhibition of PDE4 In Acrodysostosis Type2
George Baillie 1 , Elka Kyurkchieva 1 , Yuan Yan Sin 1 , Faisal Ahmed 1 , Navin Rajapakse 2 , Angela Schoolmeesters 2 , Normand Richard 2 , Paul Erdman 2 , David Hecht 2 , Aparajita Hoskote Chourasia 2 , Frank Mercurio 2 , Leah Fung 2 , Kyle Chan 2 & David Stirling 2
1University of Glasgow, Glasgow, United Kingdom; 2Biotheryx, San Diego, USA
Background: Acrodysostosis Type 2 (ACRDYS2) is a rare autosomal dominant skeletal dysplasia associated with intellectual disability and gain-of-function mutations in the phosphodiesterase type 4D gene (PDE4D) which, in turn, leads to a paucity of intracellular cAMP due to increased PDE4D activity. This increased PDE4 activity may be due to a greater existence of a mutant monomeric form of PDE4D. To date, the clinical use of PDE4 inhibitors in ACRDYS2 has been hampered by the possibility of off-target effects as there are 25 different PDE4 isoforms in humans.
Aim: To explore the utility of novel bi-functional PDE4 degrader compounds in ACRDYS2.
Methods: As PDE4 inhibitors act on all PDE4 isoforms as their catalytic sites are almost identical, a novel PDE4 bi-functional degrader was created by targeting the E3 ligase Cereblon to PDE4. To ensure selectivity, a PDE4 inhibitor was used to deliver the PROTAC complex and the ability of this complex to silence wild type and ACRDYS2 mutants of PDE4 isoforms was studied in over-expression studies using transiently transfected human embryonic kidney cells (HEK).
Results: The bi-functional degraders did not affect over-expressed, dimerised PDE4 longforms as they are sterically hindered from reaching their docking site within the PDE4 structure, however they degraded short-forms and mutated long-forms that cannot dimerise. The PDE4 degraders were effective at 10nM and worked well after 6 hours. Many of the ACRDYS2 mutations occur in the regions of the PDE4D enzyme that act as protein-protein interaction docking domains, which are vital for dimer formation. We have shown that our PDE4 degraders can target certain Acrodysostosis PDE4D mutants (e.g. T577A, PDE4D4), showing significant reductions in PDE4D protein expression via enhanced degradation. This degradation is channelled via the ubiquitin-proteosome system as it can be reversed using a proteosome inhibitor (Bortezomib). PDE4 proteolysis was induced by low nanomolar concentrations of the PDE4 degraders and was long lasting (no compensatory increases in PDE4 protein expression observed 96 hours after removal of degraders).
Conclusion: Our innovative approach represents an exciting novel therapeutic strategy for ACRDYS2 and possibly other cAMP-related developmental conditions.
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