NU 2020-137

INVENTORS
Gary Schiltz
Derek Wainwright*

SHORT DESCRIPTION
IDO-PROTAC that target immunosuppressive IDO activity via degradation

ABSTRACT
The median survival of primary GBM patients following aggressive surgical intervention, radiotherapy,chemotherapy, and tumor treating fields (TTF) is only ~14-16 months. Indoleamine 2,3-dioxygenase 1 (IDO) protein plays a critical role in the progression of GBM independent of its enzyme activity. Although the mechanism for this effect is not understood, and remains as an active area of investigation by Northwestern researchers, these data are in-line with the failed phase 3 ECHO-301/KEYNOTE-252 clinical trial suggesting a futility of IDO enzyme inhibitor treatment in patients with cancer. A more effective IDO neutralizing pharmacologic is required for abolishing its immunosuppressive effect(s). To address this need, Northwestern researchers have developed small molecule targeted degraders of IDO, termed IDO-proteolysis targeted chineras (PROTACs). These compounds bind with high affinity to IDO and recruit an E3 ubiquitin ligase that initiates polyubiquitination of IDO and causes its degradation by the proteasome. The IDO-PROTACs thereby abolish all immunosuppressive effects of IDO, including its enzyme- and non-enzyme dependent functions. The IDO-PROTACs have been initially validated in human glioblastoma cell lines, but are applicable to all forms of cancer and non-cancerous cells that also express IDO under pathologic circumstances.

APPLICATIONS

• Cancer therapeutic
• Combination Drug with immune checkpoint inhibitors to enhance anti-tumor efficacy

ADVANTAGES

• Leads to protein degradation, not just targeting enzymatic function

IP STATUS
A US patent application has been filed.

PUBLICATION
Bollu L, Wainwright D, Zhai L, Ladomersky E, Lauing K, Bell A and Schlitz G (2020) DDRE-09. Developing IDO-PROTACS to improve immunotherapeutic efficacy in patients with glioblastoma.
Neuro-Oncology 22(Suppl 2): ii63.