Abstract 3033: Bumped kinase inhibitors: A novel therapy for castration-resistant prostate cancer

Abstract

Abstract BACKGROUND: Prostate cancer (PCa) is the second most common cancer in men and one of the leading causes of cancer death. Resistance to current PCa therapies, including androgen deprivation, occurs in almost all patients leading to development of castration resistant prostate cancer (CRPC). Resistance is associated with expression of splice variants of the androgen receptor (AR-Vs) that are constitutively active. Therapies that indirectly target AR by inhibiting factors important in regulating AR levels and activity may be the most successful against these constitutively active variants. We originally designed bumped kinase inhibitors (BKIs) to inhibit Cryptosporidium sp. Further examination demonstrated that this class of BKIs also inhibits members of the mammalian protein kinase D (PKD) family. In prostate cancer, expression of all PKD isoforms has been shown to increase with cancer progression. Further, PKDs are implicated in PCa replication, migration, invasion, and progression. In regard to AR activity, studies suggest that PKDs in conjunction with heat shock protein 27 (Hsp27) are regulators of AR transport into and out of the nucleus as well as AR transcriptional activity. Such studies, suggest that targeting PKDs would affect AR signaling and thus be a promising anti-prostate cancer therapy. OBJECTIVE: To demonstrate that BKIs targeting PKD isoforms inhibit CRPC. RESULTS: Immunohistochemical staining of a tissue microarray (representing 50+ patients) with a PKD antibody demonstrated that PKD expression increased with tumor progression. On a screen of over 80 human protein kinases our BKIs inhibited members of the PKD family at low nM concentrations. Furthermore, several optimized BKI compounds, including BKI-1553, were screened against >360 human protein kinases using Cellzome’s™ inhibitor profiling methodology and only PKDs were found to be targeted significantly. This is unique from previously published BKIs, which are PKD inhibitors but also inhibit other human protein kinases such as mutated Src. In vitro our BKIs decreased proliferation of AR positive PCa cell lines but not AR negative lines. We next examined the effects of our lead compound, BKI-1553, on AR transactivation using the LNCaP cell line. BKI-1553 treated cells had decreased ARE-luciferase reporter activity. Interestingly, we also found that BKI-1553 decreased mRNA and protein levels of AR-FL and AR-V7 in these cells. In toxicity studies, BKI-1553 was non-toxic in three species at oral doses that achieved therapeutic levels. In vivo BKI-1553 significantly decreased growth of two PCa xenografts (LNCaP95, p < 0.005 and LuCaP35, p < 0.01). SUMMARY: Since we found that the PKD inhibitor BKI-1553 selectively inhibits AR positive prostate cancers, and it is thought that the majority of CRPC are AR driven, BKI-1553 could be a novel therapy for cancers that are resistant to currently available therapies. Citation Format: Cynthia C. Sprenger, Stephen Plymate, Dustin Maly, Wesley Van Voorhis, Kayode K. Ojo. Bumped kinase inhibitors: A novel therapy for castration-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3033.