thioguanine

Pharmacological inhibitors of specific USPs, such as pimozide, trifluoperazine, rottlerin, 6-thioguanine, and costunolide, are highlighted for their potential to inhibit proliferation, metastasis, induce apoptosis, and circumvent therapy resistance across breast cancer subtypes (triple-negative and HER-2 positive). The review highlights the complex and often contradictory roles of USPs in breast cancer and points to the immense promise of targeting these enzymes to develop new and efficacious anticancer therapies.

P3, N=310, Suspended, Alliance for Clinical Trials in Oncology | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

In KRAS-mutant cancer models, trametinib treatment caused dysregulation of the purine biosynthetic pathway driven by reductions in enzyme GART. This induced vulnerability nominated purine analog 6-thioguanine as a synergistic partner...In vivo, the treatment significantly increases overall survival without systemic toxicity. Integrating drug-induced multi-omic changes with functional screening identifies therapeutic strategies, supporting the use of purine analogs with MEK inhibitors for KRAS-mutant tumors.

Allopurinol co-treatment reduces toxicity while maintaining therapeutic efficacy at lower 6-MP doses. The proposed model warrants prospective evaluation for clinical relevance confirmation.

P3, N=5951, Recruiting, Children's Oncology Group | Trial completion date: Mar 2030 --> Mar 2032 | Trial primary completion date: Mar 2030 --> Mar 2032

P1/2, N=18, Completed, Kristoffer Rohrberg | Recruiting --> Completed | N=39 --> 18

Protein-protein interaction networks indicate that these variations are involved in nucleotide metabolism and pharmacological responses, confirming their role in thiopurine resistance. In summary, NT5C2 and PRPS1 gene variations may act as potential biomarkers for resistance and hence require more experimental validation of VUS to determine their significance.

P2/3, N=1708, Not yet recruiting, Children's Oncology Group | Initiation date: Mar 2026 --> Jun 2026

High-throughput drug screening identifies FK228 and thioguanine as promising therapeutic candidates, both of which show in vivo efficacy and are validated in PTEN-deleted organoids. Together, these results establish MEPP as a platform for studying PTEN-deleted ovarian cancer and provide a strategy for generating clinically relevant tumor models through targeted gene editing.

The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation.

The thiopurines 6-mercaptopurine and 6-thioguanine (TG) are analogs of guanine and are used in the treatment of hematological malignancies and immune-mediated inflammatory diseases. dMeTG could also be detected in patient samples, although in low amounts and primarily in samples with high DNA-TG levels. The developed method for the quantitation of dMeTG and dTG can be used in further studies to investigate the role of DNA-MeTG in the mechanism of action of thiopurines, including its antileukemic efficacy and effects on acquired mutations.

Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.