USP1 Program

USP1 (ubiquitin-specific protease 1) is a de-ubiquitinating enzyme that is essential for the survival and proliferation of BRCA1/2-mutant and other HRD+ (homologous recombination deficient) cancer cells, thus making USP1 inhibition synthetic lethal with BRCA1/2 mutations. Normal cells have multiple mechanisms to repair damaged DNA and prevent cell death, while BRCA 1/2 mutant cells rely on translesion synthesis and base excision repair. Inhibiting USP1 impairs translesion synthesis and thereby DNA replication, leading to cell death in BRCA1/2-mutant cancer cells. Combining USP1 and PARP inhibitors, which also impair DNA damage repair in BRCA1/2-mutant cells, demonstrate the potential for even greater benefit.

BRCA1/2 MUTATIONS (HRD+)

BRCA1/2 MUTATIONS (HRD+)

Prevent repair of double strand breaks (homologous and non-homologous end-joining)

USP1
INHIBITORS

USP1<br>INHIBITORS

Prevent efficient repair of single strand breaks (translesion synthesis)

PARP
INHIBITORS

PARP<br>INHIBITORS

Prevent efficient repair of single strand breaks (base excision repair)

Opportunity

HRD+ cancers, including BRCA1 and BRCA2-mutations, represent up to 50% of ovarian, 25% of breast, 10% of prostate and 5% of pancreatic cancers. In vivo preclinical studies for TNG348 have shown single agent efficacy and combination benefit with PARP inhibitors in BRCA1/2-mutant and other HRD+ cell-line and patient derived xenografts, including those that are intrinsically resistant to PARP inhibition.

TNG348

  • TNG348 is a synthetic lethal USP1 inhibitor that selectively kills cancer cells with HRD+-mutant cells, including BRCA1 and BRCA-2 mutations.
  • TNG348 is well tolerated at high exposures in preclinical safety studies.
  • TNG348 shows strong combination potential with from PARP inhibitors.
  • IND cleared for phase 1/2 clinical trial evaluating TNG348 as a single agent and in combination with Olaparib, a PARP inhibitor.

In vivo efficacy in PDX models

<em>In vivo</em> efficacy in PDX models
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