NCIt definition : An anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL) targeted protein degrader,
using the proteolysis targeting chimera (PROTAC) technology, with potential pro-apoptotic,
immunomodulating and antineoplastic activities. DT2216 is composed of a Bcl-XL ligand
attached to a Von Hippel-Lindau (VHL) E3 ligase ligand. Upon administration of DT2216,
the Bcl-XL binding moiety specifically targets and binds to Bcl-XL which is expressed
on tumor-infiltrating regulatory T-cells (Tregs) in the tumor microenvironment (TME)
and cancer cells that are dependent on Bcl-XL for their survival, such as certain
Bcl-XL-dependent T-cell malignancies. In turn, the VHL E3 ligase ligand is recruited
to the endoplasmic reticulum (ER) and Bcl-XL is tagged by ubiquitin. This causes ubiquitination
and proteasome-mediated degradation of Bcl-XL. The degradation of Bcl-XL leads to
an inhibition of the anti-apoptotic activity of Bcl-XL and restores apoptotic processes
in and causes depletion of Bcl-XL-expressing Tregs and Bcl-XL-dependent cancer cells.
Reduction of Tregs may activate anti-tumor CD8-positive-mediated immune responses.
This leads to the inhibition of tumor growth. Bcl-XL, a protein belonging to the Bcl-2
family, plays an important role in the negative regulation of apoptosis. Their expression
in tumors is associated with increased Tregs survival. Tregs play a key role in cancer
progression and tumor immunosuppression. Compared to other Bcl-XL inhibitors, DT2216
does not cause platelet toxicity as the VHL E3 ligase is not highly expressed in platelets.;
Semantic type(s)