ku-55933

Overview

KU-55933 (also written KU55933) is a selective, cell-permeable inhibitor of the ATM (ataxia-telangiectasia mutated) serine/threonine kinase, used widely as a tool compound to dissect ATM-dependent DNA damage response (DDR) signaling. ATM phosphorylates substrates at SQ/TQ motifs following DNA double-strand breaks (DSBs); KU-55933 competitively blocks this activity, enabling researchers to determine which phosphorylation events are ATM-mediated. It is not approved for clinical use.

Evidence in the corpus

  • Irradiation-induced pSQ/TQ phosphorylation of FLAG-tagged TRMT10A was abolished by KU-55933 treatment and by a kinase-dead ATM mutant, confirming that ATM is the primary kinase responsible for TRMT10A Ser28 phosphorylation after DNA damage in prostate cancer cells; ATR provides residual compensatory phosphorylation PMID:28068672.
  • KU-55933-mediated ATM inhibition established the epistatic relationship between ATM-mediated TRMT10A Ser28 phosphorylation and downstream BRCA1 recruitment: the S28A TRMT10A mutant (which cannot be phosphorylated) phenocopied vector-control (failed to rescue HR efficiency or BRCA1/RAD51 foci), consistent with ATM-dependent TRMT10A activation being required for BRCA1-mediated HR PMID:28068672.

Resistance mechanisms

  • ATM inhibition (modeled by KU-55933 and ATM knockdown) does not independently sensitize 22Rv1, C4-2, or DU145 mCRPC cells to PARP inhibitors, consistent with published clinical heterogeneity of ATM-loss PARPi response; the TRMT10A/USP10 axis therefore represents a distinct sensitization strategy PMID:28068672.

Cancer types (linked)

  • PRAD — KU-55933 used in mechanistic DDR experiments in mCRPC cell lines.

Sources

  • PMID:28068672 — Yang et al., TRMT10A/USP10 axis in mCRPC; KU-55933 used to confirm ATM-dependent TRMT10A Ser28 phosphorylation.

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