Triapine (3-AP)

We identified strong synergism for combined RRM2-CHK1 inhibition using the iron chelator triapine and prexasertib respectively. We confirm drug synergism in vivo in a NB zebrafish xenograft model, further underscoring the broad clinical potential of combinatorial RRM2-CHK1 inhibition. Altogether, this study paves the way for further preclinical testing of second generation RRM2 and CHK1 inhibitors such as TAS1553 and SRA737 in neuroblastoma and sarcomas.

P1, N=12, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | Trial completion date: Nov 2025 --> Dec 2026 | Trial primary completion date: Nov 2025 --> Dec 2026

In this respect, the catalytic activity of the Fe complexes of two PTSCs, Triapine (3AP) and Dp44mT, with the two most abundant reducing agents, ascorbate and glutathione, was evaluated under aerobic conditions...Thus, Fe-PTSC and Fe-PTSC2 are unlikely to drive ROS production through a direct mechanism. Instead, an indirect mechanism or a site-specific ROS production appears to be more plausible.

The anticancer thiosemicarbazone Triapine is currently in a phase III clinical trial in combination with radiation therapy and cisplatin. This, in turn, rendered cancer cells more susceptible to FASL (predominantly expressed by lymphoid immune cells)-induced caspase 8-mediated apoptosis. Consequently, our study is the first to unveil the significant role of the (adaptive) immune system in the anticancer activity of Triapine, positioning it as a promising partner for combination with immunotherapy and other immunogenic agents.

We report the synthesis and biological evaluation of disulfide-based prochelators featuring a 2-pyridyl-hydrazone motif and resulting in a tridentate (S,N,N) donor set as found in several antiproliferative chelators (e.g., Triapine, Dp44mT, DpC, COTI-2). Accordingly, the preformed iron complex FePH3 also leads to apoptosis and iron dysregulation, and its toxicity is enhanced when the antioxidant capacity of the cells is impaired. The incorporation of the 2-pyridyl-hydrazone motif in disulfide-based prochelators therefore combines iron sequestration with pro-oxidant effects that could enhance the pharmacological profile of this chelation approach for cancer applications.

The potential oncogenic effects of RRM2 in gynecologic tumor cell lines were further demonstrated using the RRM2 inhibitor Triapine (3-AP). These pro-tumorigenic effects may then be mediated through the involvement of RRM2 in the p53 and Akt/mTOR signaling pathways, altering the expression of p53 and Akt/mTOR. Thus, RRM2 is potentially a candidate gene for the unified diagnosis of cervical, endometrial, and ovarian cancers.

Our findings show that combined inhibition of RNR and WEE1 was effective against Ewing's sarcoma in vitro. They thus provide a rationale for the evaluation of the potential of combined targeting of RNR and WEE1 in Ewing's sarcoma in vivo.

While AOH generally suppressed a drug-induced activation and increased anti-inflammatory IL10 levels, DON potentiated activation and pro-inflammatory markers, such as CXCL8 and TNF in immune cells. In conclusion, AOH and DON have the potential to alter the immunological effects of anticancer therapies, which should be considered during therapy as well as in their future risk assessment.

Oral triapine is safe when given with cisplatin chemoradiation, convenient, bioavailable. Exposure is negatively impacted by smoking, and methemoglobin is a biomarker of exposure.

P1, N=30, Recruiting, Northwestern University | Active, not recruiting --> Recruiting

L6 exhibited the highest potency against skin cancer A431 cell line, with an IC50 of 0.19 μM compared to 1.8 μM with triapine and showed low toxicity against PNT-2 cells with an SI index of >100 μM. Also, it lowered the ERK1/2 expression, which affected the caspase 3 activity and showed higher binding affinity compared to the FDA-approved drug Lenalidomide in molecular docking studies. Our findings demonstrated the possible future anticancer drug potency of L6 in the skin cancer A431 cells.