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SMARCA2 PROTAC-dendrimer conjugates for the treatment of non-small cell lung cancer
Matthew O'Brien Laramy1, Rosliana Halim2, Summer Baker Dockrey3
1Synthetic Molecule Pharmaceutical Sciences, Genentech Research and Early Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.
Abstract:
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.
Insights
Dendrimer-PROTAC conjugates improve targeted protein degradation for non-small cell lung cancer treatment. This approach enhances drug delivery to tumors, reduces toxicity, and achieves sustained tumor growth inhibition.
Area of Science:
- Oncology
- Biotechnology
- Pharmacology
Background:
- Targeted protein degradation using proteolysis targeting chimeras (PROTACs) shows promise for non-small cell lung cancer (NSCLC).
- Existing SMARCA2 PROTACs exhibit limitations including rapid clearance, poor tumor distribution, and dose-limiting toxicity, hindering efficacy in preclinical models.
Purpose of the Study:
- To overcome the limitations of SMARCA2 PROTACs for NSCLC treatment.
- To develop a dendrimer-based delivery system for enhanced PROTAC efficacy and reduced toxicity.
Main Methods:
- Conjugation of SMARCA2 PROTACs to poly-L-lysine dendrimers using tunable, hydrolytically cleavable linkers.
- Evaluation of PROTAC release kinetics, systemic and tumor exposure, target degradation, and efficacy in mouse NSCLC xenograft models.
Main Results:
- PROTAC release rate from dendrimer conjugates correlated with PROTAC exposure, SMARCA2 degradation, and therapeutic efficacy.
- An optimized dendrimer-PROTAC conjugate achieved sustained tumor stasis for 21 days at a lower dose than PROTAC alone.
- The conjugate demonstrated no adverse effects, indicating an improved safety profile.
Conclusions:
- Dendrimer-based technology can effectively deliver PROTACs to solid tumors, mitigating common PROTAC liabilities.
- This strategy enhances therapeutic outcomes for NSCLC and expands the medicinal chemistry design space for PROTAC development.
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