An orally bioavailable, specific PLK1 bifunctional degrader for the treatment of small cell lung cancer and other cancers

Polo-like kinase 1 (PLK1) is a G2/M phase checkpoint protein that regulates signaling pathways critical for cell cycle progression, making it a key contributor to cancer cell proliferation and tumorigenesis. Due to its essential role across diverse cell types, PLK1 has emerged as an attractive therapeutic target for various cancers. Although several PLK1 inhibitors have reached clinical evaluation, most have failed to demonstrate efficacy at doses that show tolerable toxicity, highlighting the need for novel therapeutic approaches to effectively target PLK1. UP1002 is an orally administered, selective bifunctional PLK1 degrader which has been designed to potentially overcome such limitations. UP1002 promotes the proximity between PLK1 and cereblon (CRBN), leading to selective PLK1 degradation through a proteasome-dependent mechanism. Unlike traditional PLK1 inhibitors, UP1002 prevents PLK1 accumulation during G2/M arrest and induces robust cell cycle arrest and apoptosis. In preclinical models, UP1002 monotherapy demonstrated significant antitumor efficacy in multiple cancer types, which achieved near-complete tumor regression in a subset of dosing groups while reducing toxicity compared to canonical PLK1 inhibitors. Moreover, combinations of UP1002 with multiple approved therapies showed synergistic or additive antitumor activity, highlighting its potential to enhance current treatment regimens. Together, these findings suggest that UP1002 has therapeutic potential in small-cell lung cancer and may extend its efficacy to additional cancer types.