Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Prostate. 2024 Jul;84(10):909-921. doi: 10.1002/pros.24707. Epub 2024 Apr 15.
Lysine-specific demethylase 1 (LSD1) is emerging as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine prostate cancer (NEPC) is increasingly recognized as an adaptive mechanism of resistance in mCRPC patients failing androgen receptor axis-targeted therapies. Safe and effective LSD1 inhibitors are necessary to determine antitumor response in prostate cancer models. For this reason, we characterize the LSD1 inhibitor bomedemstat to assess its clinical potential in NEPC as well as other mCRPC pathological subtypes.
Bomedemstat was characterized via crystallization, flavine adenine dinucleotide spectrophotometry, and enzyme kinetics. On-target effects were assessed in relevant prostate cancer cell models by measuring proliferation and H3K4 methylation using western blot analysis. In vivo, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of bomedemstat are also described.
Structural, biochemical, and PK/PD properties of bomedemstat, an irreversible, orally-bioavailable inhibitor of LSD1 are reported. Our data demonstrate bomedemstat has >2500-fold greater specificity for LSD1 over monoamine oxidase (MAO)-A and -B. Bomedemstat also demonstrates activity against several models of advanced CRPC, including NEPC patient-derived xenografts. Significant intra-tumoral accumulation of orally-administered bomedemstat is measured with micromolar levels achieved in vivo (1.2 ± 0.45 µM at the 7.5 mg/kg dose and 3.76 ± 0.43 µM at the 15 mg/kg dose). Daily oral dosing of bomedemstat at 40 mg/kg/day is well-tolerated, with on-target thrombocytopenia observed that is rapidly reversible following treatment cessation.
Bomedemstat provides enhanced specificity against LSD1, as revealed by structural and biochemical data. PK/PD data display an overall safety profile with manageable side effects resulting from LSD1 inhibition using bomedemstat in preclinical models. Altogether, our results support clinical testing of bomedemstat in the setting of mCRPC.
赖氨酸特异性脱甲基酶 1（LSD1）作为转移性去势抵抗性前列腺癌（mCRPC）肿瘤进展的关键介质而崭露头角。神经内分泌前列腺癌（NEPC）越来越被认为是 mCRPC 患者对雄激素受体轴靶向治疗产生耐药性的一种适应性机制。需要安全有效的 LSD1 抑制剂来确定前列腺癌模型中的抗肿瘤反应。出于这个原因，我们对 LSD1 抑制剂 bomedemstat 进行了表征，以评估其在 NEPC 以及其他 mCRPC 病理亚型中的临床潜力。
通过结晶、黄素腺嘌呤二核苷酸分光光度法和酶动力学对 bomedemstat 进行了表征。通过使用 Western blot 分析测量增殖和 H3K4 甲基化来评估相关前列腺癌细胞模型中的靶标效应。在体内，还描述了 bomedemstat 的药代动力学（PK）和药效动力学（PD）特征。
报告了不可逆、口服生物可利用的 LSD1 抑制剂 bomedemstat 的结构、生化和 PK/PD 特性。我们的数据表明，bomedemstat 对 LSD1 的特异性超过单胺氧化酶（MAO）-A 和 -B 超过 2500 倍。bomedemstat 还对几种高级 CRPC 模型表现出活性，包括 NEPC 患者来源的异种移植物。通过测量口服给予的 bomedemstat 在体内的微量积累，实现了体内达微米级水平（在 7.5mg/kg 剂量下为 1.2±0.45µM，在 15mg/kg 剂量下为 3.76±0.43µM）。每天口服 bomedemstat 40mg/kg/天的剂量耐受性良好，观察到 LSD1 抑制导致的靶点血小板减少症，停药后迅速逆转。
结构和生化数据显示，bomedemstat 对 LSD1 的特异性增强。PK/PD 数据显示，在临床前模型中使用 bomedemstat 抑制 LSD1 具有总体安全性特征，副作用可管理。总之，我们的研究结果支持在 mCRPC 背景下对 bomedemstat 进行临床测试。
