Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• SMARCA4 mutations are common in cancer, leading to reliance on its paralog, SMARCA2.
• Selective SMARCA2 inhibition is crucial for therapeutic efficacy but challenging due to SMARCA4 homology.

Purpose of the Study:

• To discover a potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule.
• To evaluate the in vitro and in vivo efficacy of the SMARCA2-targeting PROTAC in cancer models.

Main Methods:

• Development of a SMARCA2-targeting PROTAC (A947).
• Assessment of selective SMARCA2 degradation and its impact on cancer cell growth.
• In vivo efficacy studies in SMARCA4-mutant cancer models.
• Global ubiquitin mapping and proteome profiling to assess target selectivity.

Main Results:

• A947 achieved selective SMARCA2 degradation without selective SMARCA2/4 binding.
• Potent in vitro growth inhibition and significant in vivo efficacy were observed in SMARCA4 mutant models.
• No significant off-target degradation was detected upon A947 treatment.

Conclusions:

• A non-selective SMARCA2/4 ligand was successfully transformed into a selective SMARCA2-targeting PROTAC.
• A947 demonstrates potential as a therapeutic strategy for SMARCA4-mutated cancers.
• This work offers a new therapeutic avenue for patients with SMARCA4-deficient tumors.