A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

Abstract

ABSTRACTPurposeMetastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC 1553, with antiglycolytic activity.Experimental designWe tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice was studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials.ResultsWe demonstrate a new class of small molecule inhibitors where anti-glycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy.ConclusionThis work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.Translational RelevanceThe lead compound, BKIDC-1553 demonstrates in vitro activity against most advanced prostate cancers and in vitro activity in a SCID human xenograft prostate cancer model. It also demonstrates pharmacokinetic and safety properties consistent with a late preclinical candidate that can be taken into clinical trials after good-laboratory-practice (GLP) confirmatory toxicology, formulation, and good manufacturing is performed and a FDA investigative new drug application is accepted. Since this compound has a unique mechanism of action, it will be a welcome addition to the chemotherapy of advanced prostate cancer, which generally becomes resistant to the available androgen-directed therapy, and should supplant rescue cytotoxic chemotherapy regimens that are very toxic and fail to deliver lasting response.