Structural basis for a Polθ helicase small-molecule inhibitor revealed by cryo-EM

Fumiaki Ito, Ziyuan Li, Leonid Minakhin, Gurushankar Chandramouly, Mrityunjay Tyagi, Robert Betsch, John J. Krais, Bernadette Taberi, Umeshkumar Vekariya, Marissa Calbert, Tomasz Skorski, Neil Johnson, Xiaojiang S. Chen () and Richard T. Pomerantz ()
Additional contact information
Fumiaki Ito: Los Angeles
Ziyuan Li: Los Angeles
Leonid Minakhin: Thomas Jefferson University
Gurushankar Chandramouly: Thomas Jefferson University
Mrityunjay Tyagi: Thomas Jefferson University
Robert Betsch: Fox Chase Cancer Center
John J. Krais: Fox Chase Cancer Center
Bernadette Taberi: Thomas Jefferson University
Umeshkumar Vekariya: Temple University
Marissa Calbert: Thomas Jefferson University
Tomasz Skorski: Temple University
Neil Johnson: Fox Chase Cancer Center
Xiaojiang S. Chen: Los Angeles
Richard T. Pomerantz: Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract DNA polymerase theta (Polθ) is a DNA helicase-polymerase protein that facilitates DNA repair and is synthetic lethal with homology-directed repair (HDR) factors. Thus, Polθ is a promising precision oncology drug-target in HDR-deficient cancers. Here, we characterize the binding and mechanism of action of a Polθ helicase (Polθ-hel) small-molecule inhibitor (AB25583) using cryo-EM. AB25583 exhibits 6 nM IC50 against Polθ-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 Polθ-hel:AB25583 complex structures at 3.0-3.2 Å. 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 Polθ-hel helicase via an allosteric mechanism. These detailed structural data and insights about AB25583 inhibition pave the way for accelerating drug development targeting Polθ-hel in HDR-deficient cancers.

Date: 2024
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DOI: 10.1038/s41467-024-51351-4

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