Macrocyclic Drug Discovery for DNA Polymerase Theta Inhibitors
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The Discovery of Novel Macrocyclic Inhibitors against DNA Polymerase Theta’s Polymerase Domain
DNA polymerase theta (Pol θ) has emerged as a promising therapeutic target due to its role in DNA repair and its potential relevance in cancers with homologous recombination deficiencies. This presentation highlights a macrocyclic drug discovery program focused on identifying and optimizing macrocyclic inhibitors targeting the polymerase domain of DNA polymerase theta.
Key findings from the discovery program:
- Macrocyclic drug discovery delivered potent inhibitors of the polymerase domain of DNA polymerase theta.
- Macrocyclization improved potency but generated mixtures of atropisomers.
- Introduction of an (R)-methyl group stabilized the active conformation.
- Compound 1 was identified as the leading lactam diol.
- Simplified macrocyclic inhibitors retained potency but displayed poor solubility.
- Acidic sidechains provided the most favorable balance of properties, with tetrazole 2 emerging as the most potent compound.
- Co-dosing compound 1 with niraparib did not demonstrate efficacy in a BRCA-deficient xenograft model.
- The program ultimately shifted focus from the polymerase domain to more potent helicase domain inhibitors.
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