Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific 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. We 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 and a human organoid were 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. We demonstrate a new class of small molecule inhibitors where antiglycolytic 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. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

中文翻译：

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一种抑制前列腺癌糖酵解的化合物可控制晚期前列腺癌的生长

无论最近的治疗进展如何，转移性去势抵抗性前列腺癌仍然无法治愈。随着癌症的进展，前列腺癌肿瘤表现出高度糖酵解表型。非特异性糖酵解抑制剂尚未成功用于化疗，因为它们容易引起全身毒性。本研究报告了具有抗糖酵解活性的新型小分子临床前候选药物 BKIDC-1553 的临床前活性、安全性和药代动力学。我们在体外测试了大量前列腺癌细胞系对细胞增殖的抑制作用。细胞周期、代谢和酶测定被用来证明它们的作用机制。研究了植入小鼠体内的人类 PDX 模型和人类类器官对我们的 BKIDC 临床前候选药物的敏感性。进行了一系列药代动力学实验、吸收、分布、代谢和排泄实验以及体外和体内毒理学实验，以评估临床试验的准备情况。我们展示了一类新型小分子抑制剂，其中前列腺癌细胞系中的抗糖酵解活性是通过抑制己糖激酶 2 介导的。这些化合物在多种前列腺癌模型中表现出选择性生长抑制作用。我们描述了一种先导 BKIDC-1553，它在晚期前列腺癌的临床前异种移植模型中表现出有希望的活性，相当于恩杂鲁胺。 BKIDC-1553 表现出与化合物一致的安全性和药理学特性，可用于人体研究，预期具有良好的安全裕度和预测的疗效剂量。这项工作支持在晚期前列腺癌患者的临床试验中测试 BKIDC-1553 及其衍生物。