PO.ET09.06 · 实验与分子治疗

QED-203:一种用于标准治疗耐药的晚期前列腺癌的 TRPV6 与 AR 双靶点小分子临床前候选药物

QED-203, a dual TRPV6 and AR small molecule preclinical candidate for advanced prostate cancer resistant to standard of care

编号 414 展板 17 时间 4/19 02:00–05:00 区域 Section 17 主讲 Kimberley Beaumont, PhD

分会场 Novel Antitumor Agents 1

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作者与单位 Authors & Affiliations

Kimberley Beaumont¹, Rebecca Pouwer¹, Mei Yeh¹, Melanie Robitaille², Rebecca Farrow¹, Matthew McLachlan¹, Therese Johnson¹, Akanksha Upadhyaya¹, Aaron Gregson¹, Raphael Rahmani¹, Claire Levrier¹, Hasanthi Wijesekera¹, Malika Kumasiri¹, Grant Stuchbury¹, Terrie-Anne Cock¹, Andrew Harvey¹, Gregory Monteith², Brian Dymock¹

¹QEDDI, UniQuest, University of Queensland, Brisbane, Australia,²School of Pharmacy, University of Queensland, Brisbane, Australia

摘要 Abstract

中文摘要

TRPV6 是一种钙通道,是一种在上皮性癌症(尤其是前列腺癌)中过表达的癌通道(oncochannel)。我们观察到,同时抑制 TRPV6 和 AR 在前列腺癌细胞中具有协同作用,产生强大的抗增殖效应。我们的临床前候选药物 QED-203 以低 nM 级效力抑制 TRPV6 介导的钙内流(FLIPR 和电生理学)和 NFAT 活性(NFAT 荧光素酶报告基因),并有效抑制 AR(AR 配体置换、AR 荧光素酶报告基因和易位检测)。QED-203 在对包括恩扎鲁胺(enzalutamide)在内的新一代 AR 抑制剂具有多种耐药机制的前列腺癌细胞系中保持有效性。QED-203 具有高口服生物利用度,其药代动力学特征适合每日一次给药。QED-203 在啮齿动物中耐受性良好,在去势前列腺癌小鼠模型中具有出色的体内疗效,包括一个对第一代和第二代 AR 抑制剂耐药的 PDX 模型(HID-28)。QED-203 在啮齿动物中通过尿钙水平变化以及异种移植肿瘤中与 TRPV6 和 AR 抑制一致的基因表达变化,证明了 TRPV6 靶点结合。因此,QED-203 靶向一条新型双轴通路(AR/TRPV6)以抑制前列腺癌生长。QED-203 可能为治疗已对新一代 AR 疗法产生耐药的前列腺癌患者提供新的机会,而这类患者对新型治疗方法存在明确的临床需求。

查看英文原文 English abstract

TRPV6, a calcium channel, is an oncochannel that is overexpressed in epithelial cancers, especially prostate cancer. We have observed that concomitant TRPV6 and AR inhibition is synergistic in prostate cancer cells resulting in a strong anti-proliferative effect. Our preclinical candidate QED-203 inhibits TRPV6-mediated calcium influx (FLIPR and electrophysiology) and NFAT activity (NFAT luciferase reporter) with low nM potency and potently inhibits AR (AR ligand displacement, AR luciferase reporter and translocation assay). QED-203 maintains effectiveness in prostate cancer cell lines that are resistant to next generation AR inhibitors including enzalutamide with multiple resistance mechanisms. QED-203 has high oral bioavailability with a pharmacokinetic profile amenable to once-a-day dosing. QED-203 is well tolerated in rodents with excellent in vivo efficacy in castrated mouse models of prostate cancers, including a PDX model with resistance to first and second-generation AR inhibitors (HID-28). TRPV6 target engagement has been demonstrated for QED-203 in rodents through changes in urine calcium levels, and via gene expression changes consistent with TRPV6 and AR inhibition in xenograft tumours. QED-203 thus targets a novel dual axis pathway (AR/TRPV6) to supress prostate cancer growth. QED-203 may offer a new opportunity to treat prostate cancer patients who have developed resistance to next generation AR therapies, where there is a clear clinical need for new therapeutic approaches

利益披露 Disclosure

K. Beaumont, None.. R. Pouwer, None.. M. Yeh, None.. M. Robitaille, None.. R. Farrow, None.. M. McLachlan, None.. T. Johnson, None.. A. Upadhyaya, None.. A. Gregson, None.. R. Rahmani, None.. C. Levrier, None.. H. Wijesekera, None.. M. Kumasiri, None.. G. Stuchbury, None.. T. Cock, None.. A. Harvey, None.. G. Monteith, None.. B. Dymock, None.

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