prexasertib

Overview

Prexasertib (LY2606368) is a potent, selective inhibitor of CHEK1 (Checkpoint Kinase 1), a key regulator of the DNA damage response (DDR) and replication stress checkpoint. It has been investigated as a synthetic lethal therapeutic partner for tumors harboring loss-of-function alterations in DNA repair genes.

Evidence in the corpus

  • Preferentially kills FBXO7-deficient colorectal cancer cells (A1309 CRISPR-knockout model); EC50 = 5.83 nM in FBXO7-/- versus 9.03 nM in controls. At 6.0 nM, induced a 41.6-fold increase in gamma-H2AX foci (DNA DSBs) in FBXO7-deficient cells versus 15.6-fold in controls, and a 2.6-fold increase in cleaved caspase-3 (apoptosis) PMID:36334560
  • Synergizes with 5-fluorouracil in FBXO7-deficient colorectal cancer cells within a defined concentration window (1.92–9.6 nM prexasertib + 28 micromolar 5-FU; Loewe Additivity model); antagonistic at lower 5-FU concentrations (1.1–5.6 micromolar) PMID:36334560

Resistance mechanisms

Cancer types (linked)

  • COADREAD — synthetic lethal partner for FBXO7-deficient colorectal cancer (FBXO7 copy number loss in ~32.5% of CRC)

Sources

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