Development of VN/14-1 and Related Analogs for Breast Cancer Therapy

用于乳腺癌治疗的 VN/14-1 及相关类似物的开发

• 批准号: 8657839
• 负责人: VINCENT Collins Ofuka NJAR
• 金额: $ 48.19万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657839
• 关键词: Acute Promyelocytic Leukemia; Advanced Development; Adverse effects; Adverse reactions; Agreement; All-Trans-Retinol; Androgen Receptor; Apoptotic; Applications Grants; Aromatase Inhibitors; Baltimore; Binding; Biological Availability; Biological Markers; Breast; Breast Cancer Cell; Breast Epithelial Cells; CYP17A1 gene; Cancer Cell Growth; Cancer Patient; Cancer cell line; Catabolism; Cell Cycle Arrest; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Cytochrome P450; Data; Development; Differentiation Therapy; Disease; Dose; Down-Regulation; Drug Compounding; Drug Kinetics; Drug Stability; Drug resistance; Endocrine; Ensure; Enzymes; Epidemiology; Epithelial; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogen receptor positive; Exhibits; Fibroblasts; Foundations; Generations; Goals; Growth; Half-Life; Health; Histone Deacetylase Inhibitor; Human; Hyperplasia; Imidazole; In Vitro; Incidence; Individual; Institution; Investigational Drugs; Isomerism; Isotretinoin; Lead; Legal patent; Licensing; Literature; MCF7 cell; MDA MB 231; Malignant neoplasm of prostate; Mammary gland; Maryland; Metabolic; Metabolism; Methylnitrosourea; Microarray Analysis; Modeling; Molecular Target; Mus; NCOA3 gene; Nature; Neoplasm Metastasis; Neuroblastoma; New Agents; New Drug Approvals; Oncogenes; Oral; Outcome; PC3 cell line; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plasma; Postmenopause; Prevention; Probability; Prodrugs; Property; Prospective Studies; Rattus; Refractory; Reporting; Research Design; Resistance; Resources; Retinoid Receptor; Retinoids; Role; Selective Estrogen Receptor Modulators; Solid; Tamoxifen; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicology; Tretinoin; Universities; Uterus; Vitamin A; Woman; Work; Xenograft Model; Xenograft procedure; analog; anticancer research; base; cancer therapy; capsule; design; effective therapy; enantiomer; genetic regulatory protein; hormone therapy; human study; improved; in vivo; in vivo Model; inhibitor/antagonist; malignant breast neoplasm; mortality; novel; outcome forecast; phase 1 study; pre-clinical; preclinical study; receptor; response; small molecule; success; tumor; tumor growth

DESCRIPTION (provided by applicant): Introduction: Epidemiological evidence highlights the influence of vitamin A (retinol) and its active metabolite, all-trans retinoic acid (ATRA) on the incidence of breast and prostate cancers in humans. ATRA is required for the appropriate cellular differentiation of normal human breast epithelial cells. In a 12-year prospective study of 208 postmenopausal women operated on for breast cancer, it was recently reported that low plasma retinol strongly predicts poorer prognosis in patients. Work by our group has identified novel and potent inhibitors of CYP26 enzymes responsible for intracellular catabolism of ATRA into inactive metabolites. These CYP26 inhibitors are also called retinoic acid metabolism blocking agents (RAMBAs). Our novel agents, in addition to inhibiting ATRA metabolism, also possess multiple desirable anti-breast cancer properties, and hence are called atypical RAMBAs. Our lead compound, 4-(1)-(1H-imidazol-1-yl)-(E)-retinoic acid (VN/14-1) exhibits exceptional anti-tumor efficacy in several endocrine-sensitive and insensitive (i.e., tumors that are resistant to mainstay breast cancer therapies such as tamoxifen and aromatase inhibitors) breast cancer xenograft models. VN/14-1 also inhibits the growth of tumors in the N-methyl-N-nitrosourea (MNU)-induced estrogen receptor (ER) positive rat mammary model and antagonizes the stimulatory effect of estradiol on the uterus. In contrast to its effects on several breast cancer cell lines, the compound exhibits virtually no growth inhibition (at concentrations up to 100 ?M) of normal human breast epithelial and fibroblast cells. The University of Maryland, Baltimore (UMB, the PI's former institution) has entered into a clinical research agreement with Cancer Research UK (CRUK) to conduct the first in human study of VN/14-1. Chesapeake BioDiscovery Management LLC (CBDM), Baltimore has recently licensed the entire RAMBAs technology from UMB. It may also be relevant to state here that in another project, a CYP17 inhibitor /androgen receptor modulator, VN/124-1 (now called TOK-001) invented by the PI of this application recently received FDA investigational new drug (IND) approval for phase I/II clinical trials in prostate cancer patients. Although VN/14-1 has outstanding oral bioavailability (%F >100%) in rat and anti-tumor efficacy, it has a short half-life of 0.34 and 1.41 hr, in mouse and rat, respectively. Therefore, in this application, one of our goals is to design and synthesize new analogs with improved in vivo stability and with anti-breast cancer activities as VN/14-1 or better. We envision that such agent would possess enhanced efficacy and a larger therapeutic index than VN/14- 1. In addition, we propose to investigate the therapeutic potential and mechanisms of action the new lead compounds and either of the two enantiomers of VN/14-1, i.e., (+) and (-)-VN/14-1. This strategy is based on several literature precedents which show that the enantiomers in a chiral compound/drug generally show significant differences in their pharmacokinetics (PK), pharmacodynamics (PD) and adverse reactions. Therefore, it is important to know the individual isomer effects on the potency, drug-likeness and efficacy so that we can avoid the adverse effects of the other isomer, if any. Hypothesis: Using our lead racemic VN/14-1, we have established proof-of-principle of the efficacy of this class of RAMBAs in many in vitro and in vivo models of human and murine breast cancers. The major hypothesis to be tested as described in this revised application is that development (identification) of 2nd generation atypical RAMBAs, new analogs of VN/14-1 with enhanced metabolic stability, drug-likeness and efficacy can potentially be developed as new therapy for breast cancer (inhibition of tumor growth and metastasis). Objectives: To test this hypothesis, and to maximize the probability of achieving our ultimate goal while using resources most efficiently, we will carry out four specific aims: 1) To synthesize enantiomers of lead VN/14-1 and to modify VN/14-1 to produce more potent/metabolically stable/efficacious drug-like analogs; 2) To extensively characterize and evaluate new analogs as RAMBAs and as anti-proliferative agents of human breast cancer cells; 3) To determine the mechanism of action of the lead compound and best analogs in human breast cancer cell line; and 4) To test the lead compound and best analogs for their ability to inhibit breast cancer growth, inhibit breast cancer metastasis in vivo and identify markers of efficacy. Significance: Our ultimate goal is to discover and develop new orally active drugs for breast cancer capable of inhibiting the growth of tumor cells and metastasis. Importantly, the atypical RAMBAs inhibit both endocrine- sensitive and endocrine resistant (refractory to endocrine therapies) breast cancers, and also antagonize uterine hyperplasia, characteristics that are distinct from those of selective estrogen receptor modulators (SERMs), such as tamoxifen and aromatase inhibitors (AIs). The proposed studies if successfully conducted will identify at least one or two highly optimized, orally efficacious atypical RAMBAs suitable for advanced preclinical development for breast cancer therapy. The studies would also lead to the identification of biomarkers that would be useful in clinical trials.

描述（由申请人提供）： 简介：流行病学证据强调维生素 A（视黄醇）及其活性代谢物全反式视黄酸 (ATRA) 对人类乳腺癌和前列腺癌发病率的影响。 ATRA 是正常人乳腺上皮细胞适当细胞分化所必需的。在一项对 208 名接受乳腺癌手术的绝经后妇女进行的为期 12 年的前瞻性研究中，最近报道称，低血浆视黄醇强烈预示着患者预后较差。我们小组的工作已经确定了新型有效的 CYP26 酶抑制剂，该酶负责 ATRA 细胞内分解代谢为无活性代谢物。这些 CYP26 抑制剂也称为视黄酸代谢阻断剂 (RAMBA)。我们的新型药物除了抑制 ATRA 代谢外，还具有多种理想的抗乳腺癌特性，因此被称为非典型 RAMBA。我们的先导化合物 4-(1)-(1H-咪唑-1-基)-(E)-视黄酸 (VN/14-1) 在多种内分泌敏感和不敏感（即肿瘤）中表现出卓越的抗肿瘤功效对主要乳腺癌疗法（如他莫昔芬和芳香酶抑制剂）具有耐药性的乳腺癌异种移植模型。 VN/14-1 还可抑制 N-甲基-N-亚硝基脲 (MNU) 诱导的雌激素受体 (ER) 阳性大鼠乳腺模型中肿瘤的生长，并拮抗雌二醇对子宫的刺激作用。与它对几种乳腺癌细胞系的作用相反，该化合物对正常人乳腺上皮细胞和成纤维细胞几乎没有生长抑制作用（浓度高达 100 µM）。马里兰大学巴尔的摩分校（UMB，PI 的前身机构）已与英国癌症研究中心 (CRUK) 签订临床研究协议，开展 VN/14-1 的首次人体研究。巴尔的摩切萨皮克生物发现管理有限责任公司 (CBDM) 最近从 UMB 获得了整个 RAMBA 技术的许可。这里还可能需要说明的是，在另一个项目中，该申请的 PI 发明的 CYP17 抑制剂/雄激素受体调节剂 VN/124-1（现称为 TOK-001）最近获得了 FDA 在研新药（IND）批准用于前列腺癌患者的 I/II 期临床试验。尽管 VN/14-1 在大鼠中具有出色的口服生物利用度 (%F >100%) 和抗肿瘤功效，但其在小鼠和大鼠中的半衰期较短，分别为 0.34 小时和 1.41 小时。因此，在这一应用中，我们的目标之一是设计和合成具有改善的体内稳定性和抗乳腺癌活性的新类似物如VN/14-1或更好。我们预计这种药物将比 VN/14-1 具有更强的功效和更大的治疗指数。此外，我们建议研究新的先导化合物和 VN/14- 的两种对映体之一的治疗潜力和作用机制。 1，即(+)和(-)-VN/14-1。该策略基于多个先例文献，这些先例表明手性化合物/药物中的对映体通常在药代动力学 (PK)、药效学 (PD) 和不良反应方面表现出显着差异。因此，了解单个异构体对效力、药物相似性和功效的影响非常重要，这样我们就可以避免其他异构体（如果有）的不利影响。假设：使用我们的主要外消旋 VN/14-1，我们已经在人类和小鼠乳腺癌的许多体外和体内模型中建立了此类 RAMBA 功效的原理证明。本修订申请中所描述的待测试的主要假设是，开发（鉴定）第二代非典型 RAMBA、VN/14-1 的新类似物，具有增强的代谢稳定性、药物相似性和功效，有可能被开发为新疗法乳腺癌（抑制肿瘤生长和转移）。目标：为了检验这一假设，并在最有效地利用资源的同时最大限度地提高实现最终目标的可能性，我们将实现四个具体目标：1）合成先导物 VN/14-1 的对映体并修饰 VN/14- 1 生产更有效/代谢稳定/有效的药物类似物； 2) 广泛表征和评估作为 RAMBA 的新类似物以及作为人类乳腺癌细胞的抗增殖剂； 3) 确定先导化合物和最佳类似物在人乳腺癌细胞系中的作用机制； 4) 测试先导化合物和最佳类似物抑制乳腺癌生长、体内抑制乳腺癌转移的能力并确定功效标记物。意义：我们的最终目标是发现和开发能够抑制肿瘤细胞生长和转移的新型口服活性乳腺癌药物。重要的是，非典型 RAMBA 可以抑制内分泌敏感型和内分泌抵抗型（内分泌治疗难治性）乳腺癌，并且还可以拮抗子宫增生，这些特性不同于选择性雌激素受体调节剂（SERM），例如他莫昔芬和芳香酶抑制剂。 AI）。拟议的研究如果成功进行，将鉴定出至少一到两种高度优化、口服有效的非典型 RAMBA，适合乳腺癌治疗的高级临床前开发。这些研究还将确定可用于临床试验的生物标志物。

项目成果

Novel galeterone analogs act independently of AR and AR-V7 for the activation of the unfolded protein response and induction of apoptosis in the CWR22Rv1 prostate cancer cell model.

新型伽莱特酮类似物独立于 AR 和 AR-V7 发挥作用，在 CWR22Rv1 前列腺癌细胞模型中激活未折叠蛋白反应并诱导细胞凋亡。

• 发表时间: 2017-10-24
• 作者: McCarty, David J;Huang, Weiliang;Kane, Maureen A;Purushottamachar, Puranik;Gediya, Lalji K;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O

Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments.

• DOI: 10.4155/fmc.10.14
• 发表时间: 2010-04-06
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: T. Vasaitis;V. Njar
• 通讯作者: V. Njar

Murine toxicology and pharmacokinetics evaluation of retinoic acid metabolism blocking agent (RAMBA), VN/12-1.

视黄酸代谢阻断剂（RAMBA）VN/12-1的小鼠毒理学和药代动力学评价。

• 发表时间: 2012-08
• 影响因子: 3
• 作者: Godbole, Abhijit M;Purushottamachar, Puranik;Martin, Marlena S;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O

A new simple and high-yield synthesis of 5α-dihydrotestosterone (DHT), a potent androgen receptor agonist.

5α-二氢睾酮 (DHT) 的一种新的简单高产合成方法，5α-二氢睾酮 (DHT) 是一种有效的雄激素受体激动剂。

• 发表时间: 2012-12
• 影响因子: 2.7
• 作者: Purushottamachar, Puranik;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O

Novel C-4 heteroaryl 13-cis-retinamide Mnk/AR degrading agents inhibit cell proliferation and migration and induce apoptosis in human breast and prostate cancer cells and suppress growth of MDA-MB-231 human breast and CWR22Rv1 human prostate tumor xenogra

新型 C-4 杂芳基 13-顺式-视黄酰胺 Mnk/AR 降解剂抑制细胞增殖和迁移，诱导人乳腺癌和前列腺癌细胞凋亡，并抑制 MDA-MB-231 人乳腺癌和 CWR22Rv1 人前列腺肿瘤异种瘤的生长

• 发表时间: 2015-02-26
• 影响因子: 7.3
• 作者: Mbatia, Hannah W;Ramalingam, Senthilmurugan;Ramamurthy, Vidya P;Martin, Marlena S;Kwegyir;Njar, Vincent C O
• 通讯作者: Njar, Vincent C O