9bp9

Publication Abstract from PubMed

DNA polymerase theta (Poltheta) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Poltheta is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Poltheta helicase (Poltheta-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC(50) against Poltheta-hel, selectively kills BRCA1/2-deficient cells, and acts synergistically with olaparib in cancer cells harboring pathogenic BRCA1/2 mutations. Cryo-EM uncovers predominantly dimeric Poltheta-hel:AB25583 complex structures at 3.0-3.2 A. The structures reveal a binding-pocket deep inside the helicase central-channel, which underscores the high specificity and potency of AB25583. The cryo-EM structures in conjunction with biochemical data indicate that AB25583 inhibits the ATPase activity of Poltheta-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Poltheta-hel in HDR-deficient cancers.

Structural basis for a Poltheta helicase small-molecule inhibitor revealed by cryo-EM.,Ito F, Li Z, Minakhin L, Chandramouly G, Tyagi M, Betsch R, Krais JJ, Taberi B, Vekariya U, Calbert M, Skorski T, Johnson N, Chen XS, Pomerantz RT Nat Commun. 2024 Aug 14;15(1):7003. doi: 10.1038/s41467-024-51351-4. PMID:39143110^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.