The traditional approach to development of therapeutics is aimed at regulating the activity
of proteins with the use of small-molecule inhibitors. The limitation of such an approach is
the need for an appropriate binding site, which around 80 % of the human proteome does
not exhibit, thus making them undruggable with such inhibitors. A new method of targeted
protein degradation could provide the solution with the use of heterobifunctional molecules
(PROTACs) which hijack the body's endogeneous mechanism for protein degradation.
These chimeric molecules are comprised of three parts: E3 ligase ligand, target protein ligand
and a linker. The effectiveness lies in their mechanism of action and catalytic nature, which
allows them to induce targeted protein degradation with only transient interactions with
protein at low concentrations. For these reasons, chimeric degraders showed usefulness in
the field of oncology as they can circumvent certain resistance mechanisms due to their mode
of action. One of many important targets in oncology are inhibitor of apoptosis (IAP)
proteins, which play a key role inhibiting cell apoptosis. Scientists have uncovered that these
proteins are overly expressed inside cancerous tissue and are associated with bad prognosis,
disease progression and low response to treatment. Therefore, IAP proteins represent
interesting targets for potential cancer treatment.
In the scope of this thesis, we synthesised a chimeric degrader which incorporates ligands
for ligases cereblon and IAP that were connected via a linker. Our heteroPROTAC was
tested on a multiple myeloma cell line MM.1S with the method of western blotting, and
showed concentration-dependent selective degradation of XIAP, an important member of
the IAP protein family. At higher concentrations, we observed elimination of all IAP proteins
tested, as well as partial degradation of transcription factor IKZF3. The protein levels of
ligase cereblon remained unaltered, confirming the unilateral degradation of IAP proteins.
Protein depletion was also demonstrated with the use of global proteomic analysis, where a
selective reduction of XIAP protein levels was shown. The synthesised degrader represents
both a useful probe for future research of the involvement of IAP proteins in the pathogenesis
of malignant diseases, as well as a good starting point for further therapeutic development.
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