SMARCA2 PROTAC-dendrimer conjugates for the treatment of non-small cell lung cancer.

Targeted protein degradation of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) with proteolysis targeting chimeras (PROTACs) represents a promising approach for the treatment of non-small cell lung cancer (NSCLC). SMARCA2 PROTACs have been reported with sufficient potency and selectivity to drive in vitro activity, however their rapid clearance from systemic circulation, limited tumor distribution, and dose-limiting toxicity prevented sustained tumor growth inhibition in mouse NSCLC xenograft models. To overcome these issues, we conjugated known SMARCA2 PROTACs to poly-L-lysine dendrimers via hydrolytically cleavable linkers with tunable release rates. We found that the PROTAC release rate from the dendrimer conjugate correlated with the systemic and tumor exposure of the free PROTAC, SMARCA2 degradation in tumor and downstream target modulation, and efficacy in a mouse NSCLC xenograft model. A single dose of an optimized dendrimer-PROTAC conjugate achieved tumor stasis up to 20 days at a significantly lower dose than the PROTAC alone, with no adverse effects. This work highlights the potential of dendrimer-based technologies to deliver PROTACs to solid tumors, to mitigate common PROTAC liabilities, and to enable the use of PROTACs from a broader medicinal chemistry design space.