Date of Award

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Amarnath Natarajan

Abstract

IKKβ is a key kinase in the canonical NF-κB pathway. Transient activation of IKKβ is required for normal immune response while sustained activation has been implicated in cancer. To date, no IKKβ inhibitor has been approved for clinical use as a chemotherapeutic, likely due to unexpected toxicities associated with blocking the transient activation of IKKβ. We hypothesized that an IKKβ inhibitor that allows transient activation of IKKβ, but not sustained activation of IKKβ, could inhibit cancer growth without inducing toxicity.

As such, we identified a small molecule inhibitor, 13-197, that allows the transient activation of IKKβ but not the sustained activation of IKKβ. 13-197 inhibits cancer growth without inducing toxicity. Structure activity relationship studies (SAR) were conducted with 13-197 analogs to determine substituents key for activity against IKKβ-mediated NF-κB activity and the anticancer effects of 13-197 were studied in pancreatic cancer cells. 13-197 inhibited NF-κB pathway proteins and decreased the expression of anti-apoptotic proteins.

To further explore options for the development of non-toxic IKKβ inhibitors, 25-4 was designed to feature the a-methylene-g-butyrolactone targeting motif of the IKKβ and NF-κB inhibitor parthenolide. Parthenolide is active against IKKβ and NF-κB in cell-based studies but the drug has not been approved as an anticancer treatment despite its effects in cells and lack of toxicity in clinical trials. SAR studies with 25-4 identified structural features key to the small molecule’s activity and click chemistry with a 25-4 analog verified the molecule’s activity towards IKKβ and NF-κB. Cell-based studies with 25-4 demonstrate the molecule’s anticancer activities, such as growth inhibition, inhibition of colony formation and induction of apoptosis. Furthermore, 25-4 synergized with the clinical chemotherapeutic cisplatin to inhibit the viability of cancer cells. Future studies will elucidate the mechanistic basis for non-toxic inhibition of IKKβ by 25-4 and will focus on improving the drug-like properties of the small molecule.

Overall, these studies demonstrate that IKKβ is a viable target for anticancer treatment and establish 13-197 and 25-4 as novel inhibitors of IKKβ with IC50s comparable to known IKKβ inhibitors and synergistic activity with clinically-relevant chemotherapeutics.

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