Small Molecule Inhibitors of Thioredoxin Reductase as Cancer Therapeutics

University of Pittsburgh
posted on 01/06/2010

Investigators have discovered novel palmarumycin analogs. These analogs inhibit the thioredoxin/thioredoxin reductase (Trx/TrxR) system which leads to marked inhibition of tumor growth as a treatment for cancer.

Suggested Uses

Anti-cancer agent active against multiple tumor types
Potential utility in the treatment of other diseased states including:
1) Diabetic neuropathy
2) Rheumatoid arthritis
3) Sjogren’s syndrome
4) AIDS
5) Reperfusion injury

Advantages

Candidate first in class molecule targeting Thioredoxin reductase
Water soluble prodrug that is rapidly converted into the active drug at physiological pH and in plasma
Active against multiple human tumor types
o Breast Cancer
o Rhabdomyosarcoma
o Small Cell Lung Cancer

Innovation Details

Detailed Description

Investigators have developed PX-916, a water soluble prodrug of Palmarumycin CP1, a natural
product inhibitor of Thioredoxin reductase. In its natural form, the utility of Palmarumycin CP1 is limited by its water solubility, which therefore impacts its bioavailability. PX-916 is converted to active drug at physiological pH but is stable at acid pH. PX-916 demonstrates excellent antitumor activity both in vitro and in vivo in multiple human tumor xenograft models.

Background
Thioredoxin-1, a redox protein involved in regulating cell division, is often overexpressed in tumors. This overexpression results in growth of the cancerous tissue and is associated with a decrease in patient survival. Due to the role of Thioredoxin-1 in the growth and survival of tumors, small molecule inhibitors targeting Thioredoxin reductase may be potential anti-cancer agents.

Thioredoxin reductase may also play an important role in other disease states including diabetic neuropathy, rheumatoid arthritis, Sjogren’s syndrome, AIDS, and reperfusion injury.

Stage of Development