Accelerating Discovery Success With Structure-Guided Drug Design: A Worked Example From A Challenging DNA-Repair Target, Artemis

By Mary Rosenblum, Ph.D., and Douglas B. Kitchen, Ph.D.

Targeting Artemis, a critical DNA‑repair nuclease implicated in cancer resistance, has long posed challenges due to poor protein tractability and limited structural insight. This work demonstrates how an integrated, structure‑enabled discovery approach can overcome those barriers. Through successful expression and crystallization of full‑length Artemis, researchers generated the first co‑crystal structures of inhibitor–protein complexes, enabling direct visualization of binding interactions.

High‑throughput screening of a diverse, lead‑like compound library uncovered unexpected non‑metal‑binding inhibitors that engage a novel distal site distinct from the catalytic center. Structural analysis revealed subtle but reproducible conformational shifts that proved essential for potency and selectivity. Guided by more than 80 co‑crystal structures, collaborative medicinal, computational, and structural chemistry efforts rapidly refined multiple hit series.

This iterative, data‑driven strategy transformed weak initial hits into low‑nanomolar inhibitors, delivering new chemical matter and validating Artemis as a druggable target—highlighting the power of crystallography‑led SAR in accelerating discovery against complex enzymes.