Bumped-Kinase Inhibitors as Castrate-Resistant Prostate Cancer Drugs
Abstract
The objective of this project is to develop a selective small molecule inhibitor of protein kinases to treat advanced prostate cancer. The rationale for this project is that protein kinases are commonly upregulated in prostate cancer patients and inhibition of kinases may result in tumor suppression. At the University of Washington, our group has been instrumental in developing a group of kinase inhibitors called ?bumped kinase inhibitors? (BKI). The bump refers to a specific aspect of their structure that enhances their specificity and leads to fewer off-target effects. From the 600 BKIs that we have developed, we have determined that there is a group of our BKIs that have a unique structure-activity-relationship (SAR) that makes them effective at inhibiting the proliferation of prostate cancer cells that express the androgen receptor. This is important because in spite of new therapies such as abiraterone and enzalutamide, which are directed at the androgen receptor, the cancer recurs in 90 percent of patients and in the majority of these men continues to be driven by some version of the androgen receptor. Our lead BKIs have shown significant activity against full-length androgen receptor-driven tumors as well as tumors resistant to current therapies that are driven by constitutively active forms of the androgen receptor. The structure of our BKIs also restricts their activity against a narrow range of kinases and limits their toxicity. Our lead BKIs are orally bioavailable, active in low doses, and do not affect non-malignant prostate epithelial cells or androgen receptor-negative tumors. We hypothesize (1) that BKIs are specific candidates for treatment of advanced prostate cancer that is androgen receptor-driven and (2) that BKIs work as kinase inhibitors and act directly or indirectly by inhibition of the androgen receptor. This proposal will speed the development of BKIs as a new drug for use against prostate cancer by (1) establishing the mechanism(s) of action of BKIs, (2) further developing potent BKIs for advanced prostate cancer while retaining minimal off-target activity, and (3) analyzing leads for potency, efficacy, and safety to progress the optimal leads to a preclinical candidate and a back-up molecule. This program will benefit patients with advanced prostate cancer by bringing new compounds against new targets into the clinic. We expect our BKIs to be effective against advanced prostate cancer as long as it is driven by the androgen receptor. This makes BKIs applicable to over 90 percent of men with recurrent disease. The potential clinical applications are the rapid development of new compounds to treat prostate cancer that benefit patients by selective inhibition of tumor progression molecules. The risks appear small; however, off-target effects of kinase inhibitors can have unexpected toxicity. The advantage of our compounds is that they are highly selective and appear to inhibit few off-target kinases. There has been no sign of toxicity at effective treatment doses in multiple preclinical models with up to 8 weeks of therapy. Given the current state of development of our inhibitors, we anticipate obtaining Investigational New Drug (IND) status within 1 year of completion of this project. IND status will allow the BKIs to then be moved into Phase 1 clinical trials. The likely contribution of this project to prostate cancer is that we have a lead compound that inhibits select kinases, which then downregulates the androgen receptor. Development of compounds by this proposal should rapidly lead to a clinical trial to determine the efficacy of BKIs in advanced prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710325
Entities
People
- Wesley Van Voorhis
Organizations
- United States Army
- University of Washington