APR-246 and DNA polymerase theta inhibitor Novobiocinsynergize to eliminate TP53 mutant AML cells

Novobiocin synergizes with APR-246 to eliminate TP53-mutant AML cells, showing strong synergy across isogenic MOLM13 lines carrying common TP53 variants.

• Why it matters: TP53-mutant MDS/AML patients have poor outcomes and APR-246 combinations with azacitidine failed to meet efficacy endpoints, motivating more effective strategies.
• What they did: In isogenic MOLM13 AML cell lines with shared TP53 variants, the APR-246 active form MQ (via formaldehyde) creates DNA-protein crosslinks, and DNA polymerase theta inhibition by Novobiocin was tested for synergy.
• The result: The APR-246–Novobiocin combination induced AML cell death with strong synergy in all TP53-mutant lines and lesser effects in TP53 wildtype/null cells, and it produced potent in vitro growth inhibition of primary TP53-mutated AML/CMML samples at low micromolar or nanomolar APR-246.

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