Discovery of Potent OTUB1/USP8 Dual Inhibitors Targeting Proteostasis in Non-Small-Cell Lung Cancer

Deubiquitinating enzymes (DUBs) are key regulatory components
of
the ubiquitination system. Many DUBs have been revealed to play key
roles in normal physiology and diseases. However, only very limited
DUB members have well-characterized inhibitors. OTUB1 and USP8 are
two DUBs reported to promote both immune evasion and tumorigenesis
in tumor models, yet their targeted inhibitors are in the early stages
of development. Here, we describe the lead identification and optimization
of an OTUB1/USP8 dual inhibitor, 61, which exhibits highly
potent and selective inhibition of both targets with subnanomolar
IC50s in vitro. By inhibiting both DUBs, 61 phenocopies the double knockdown of OTUB1/USP8 and exerts
pronounced antiproliferative effects in H1975 and other non-small-cell
lung cancer (NSCLC) cell lines. Moreover, 61 efficaciously
mitigates tumor growth in vivo. Collectively, our
results provide a useful tool for pharmacological perturbation of
OTUB1/USP8 and introduce a promising therapeutic strategy of dual
DUB inhibition for treating NSCLC.