spautin-1

Overview

Spautin-1 is a tool-compound inhibitor of the deubiquitinases USP10 and USP13. In the context of DNA damage response (DDR) research, it was identified as an inhibitor of USP10, which stabilizes the tRNA methyltransferase TRMT10A—a non-canonical regulator of homologous recombination (HR) that recruits BRCA1 to DNA double-strand breaks via ATM-mediated Ser28 phosphorylation. By inhibiting USP10, spautin-1 promotes proteasomal degradation of TRMT10A, induces “BRCAness” in HR-proficient tumors, and sensitizes cells to PARP inhibitors such as olaparib. No clinical-grade USP10 inhibitor based on spautin-1 currently exists; its pharmacokinetics and on-target specificity in humans remain to be established.

Evidence in the corpus

  • In BRCA1/2-wild-type mCRPC cell lines (22Rv1, C4-2) and two patient-derived xenograft models (PDX#546, PDX#1092) with high USP10/TRMT10A expression, spautin-1 (20 mg/kg in vivo) combined with olaparib produced HSA synergy scores >10, CI=0.76 in 22Rv1 CDX, and 42.9% additional tumor-volume reduction vs olaparib alone in PDX#1092; the combination was well-tolerated in C57BL/6 mice with no additional hematologic toxicity beyond olaparib monotherapy PMID:28068672.
  • Spautin-1 dose-dependently reduced TRMT10A protein in 22Rv1 cells (rescued by the proteasome inhibitor MG-132, confirming proteasome-dependent degradation), decreased HR efficiency (DR-GFP reporter), and reduced BRCA1/RAD51 foci without affecting upstream DDR signaling (gamma-H2AX, 53BP1) PMID:28068672.
  • Synergy with olaparib was confirmed in BRCA2-WT-overexpressing 22Rv1 cells, demonstrating that the effect is independent of the line’s monoallelic BRCA2 T3033Nfs*11 background PMID:28068672.

Resistance mechanisms

  • USP10 deep deletion (~10% of SU2C/PCF mCRPC cohorts) may create an intrinsically PARPi-sensitive state independently of spautin-1 treatment; conversely, high USP10/TRMT10A co-expression is hypothesized to confer intrinsic resistance to PARPi that spautin-1 can overcome PMID:28068672.

Cancer types (linked)

  • PRAD — tested in mCRPC cell lines and PDX models; TRMT10A/USP10 axis validated as PARPi-sensitizing target.

Sources

  • PMID:28068672 — Yang et al., TRMT10A/USP10 axis in mCRPC; spautin-1 as USP10 inhibitor synergizing with olaparib.

This page was processed by crosslinker on 2026-05-14.