Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A

Ivan Hernandez; Ethan Ward; Thomas R R Pettus; Norbert O Reich

doi:10.1021/acsmedchemlett.3c00528

Structural Investigations of Phthalazinone Derivatives as Allosteric Inhibitors of Human DNA Methyltransferase 3A

ACS Med Chem Lett. 2024 Apr 8;15(5):590-594. doi: 10.1021/acsmedchemlett.3c00528. eCollection 2024 May 9.

Authors

Ivan Hernandez¹, Ethan Ward¹, Thomas R R Pettus¹, Norbert O Reich^{1

2}

Affiliations

¹ Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106-9510, United States.
² Biomolecular Science and Engineering, University of California, Santa Barbara, California 93106-9510, United States.

Abstract

The development of new therapeutics targeting enzymes involved in epigenetic pathways such as histone modification and DNA methylation has received a lot of attention, particularly for targeting diverse cancers. Unfortunately, irreversible nucleoside inhibitors (azacytidine and decitabine) have proven highly cytotoxic, and competitive inhibitors are also problematic. This work describes synthetic and structural investigations of a new class of allosteric DNA methyltransferase 3A (DNMT3A) inhibitors, leading to the identification of several critical pharmacophores in the lead structure. Specifically, we find that the tetrazole and phthalazinone moieties are indispensable for the inhibitory activity of DNMT3A and elucidate other modifiable regions in the lead compound.