Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

Proteolysis-targeting
chimera (PROTAC) is an attractive technology
in drug discovery. Canonically, targets act as a basic starting point
in the most previous PROTAC design. Here, we designed degraders considering
from the view of clinical benefits. With this novel design, Brigatinib
was turned into a degrader SIAIS164018 and endowed with unique features.
First, SIAIS164018 could degrade not only ALK fusion proteins in activating
or G1202R-mutated form but also mutant EGFR with L858R + T790M, which
are two most important targets in non-small-cell lung cancer. Second,
SIAIS164018 strongly inhibited cell migration and invasion of Calu-1
and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several
important oncoproteins involved in metastasis such as FAK, PYK2, and
PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile
when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable
and well tolerated in vivo. SIAIS164018 is an enlightening degrader
for us to excavate the charm of protein degradation.