Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions

Heterobifunctional degraders, known as proteolysis targeting
chimeras
(PROTACs), theoretically possess a catalytic mode-of-action, yet few
studies have either confirmed or exploited this potential advantage
of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions
were developed by conjugating ALK inhibitors to cereblon ligands.
Simultaneous optimization of pharmacology and compound properties
using ternary complex modeling and physicochemical considerations
yielded multiple catalytic degraders that were more resilient to clinically
relevant ATP-binding site mutations than kinase inhibitor drugs. Our
strategy culminated in the design of the orally bioavailable derivative
CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs),
degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo,
and commensurately slowed tumor growth, while the third generation
ALK inhibitor drug lorlatinib had no effect. These results validate
our original therapeutic hypothesis by exemplifying opportunities
for catalytic degraders to proactively address binding site resistant
mutations in cancer.