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.

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维甲酸(ATRA)对人类乳腺癌和前列腺癌发病率的影响。全反式维甲酸是正常人类乳腺上皮细胞适当分化所必需的。在一项对208名绝经后乳腺癌手术妇女进行的12年前瞻性研究中，最近有报道称，低血浆视黄醇强烈预示着患者更差的预后。我们小组的工作已经确定了新型和有效的细胞色素P26酶抑制剂，该酶负责将ATRA在细胞内分解为不活跃的代谢物。这些CYP26抑制剂也被称为维甲酸代谢阻滞剂(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)-维甲酸(VN/14-1)在几种内分泌敏感和不敏感(即对三苯氧胺和芳香酶抑制剂等主流乳腺癌治疗方法耐药的肿瘤)乳腺癌移植模型中显示出出色的抗肿瘤效果。在N-甲基-N-亚硝脲(MNU)诱导的雌激素受体(ER)阳性的大鼠乳腺模型中，VN/14-1也能抑制肿瘤的生长，并拮抗雌激素对子宫的刺激作用。与其对几种乳腺癌细胞株的作用相比，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100M)。位于巴尔的摩的马里兰大学(UMB)与英国癌症研究中心(CRUK)达成了一项临床研究协议，将对VN/14-1进行首个人体研究。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。这里可能还需要说明的是，在另一个项目中，由本申请的PI发明的CYP17抑制剂/雄激素受体调节剂VN/124-1(现在称为TOK-001)最近获得了FDA批准用于前列腺癌患者的I/II期临床试验的研究新药(IND)。虽然VN/14-1在大鼠体内具有良好的口服生物利用度(%F&gt；100%)和抗肿瘤效果，但在小鼠和大鼠体内的半衰期较短，分别为0.34和1.41小时。因此，在这项应用中，我们的目标之一是设计和合成具有更好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具有更强的疗效和更大的治疗指数。此外，我们还建议研究新的先导化合物和VN/14-1的两个对映体之一，即(+)和(-)-VN/14-1的治疗潜力和作用机制。这一策略基于几个文献先例，这些文献表明，手性化合物/药物中的对映体在药代动力学(PK)、药效学(PD)和不良反应方面通常表现出显著的差异。因此，了解不同的异构体对药物效力、类药物和药效的影响是很重要的，这样我们就可以避免其他异构体的不良影响。假设：使用我们的先导外消旋VN/14-1，我们已经建立了这类RAMBA在许多体外和体内人类和小鼠乳腺癌模型中有效性的原则证明。本修订申请中描述的需要检验的主要假设是，开发(鉴定)第二代非典型RAMBA，即具有增强的代谢稳定性、药物相似性和有效性的VN/14-1的新类似物，可能会被开发为乳腺癌的新疗法(抑制肿瘤生长和转移)。目的：为了验证这一假说，并在最有效地利用资源的同时最大限度地实现我们的最终目标，我们将实现四个具体目标：1)合成VN/14-1的对映体，并对VN/14-1进行修饰，以产生更有效的/代谢稳定的/有效的类药物类似物；2)广泛表征和评价作为RAMBA和抗乳腺癌细胞增殖剂的新类似物；3)确定先导化合物和最佳类似物在人乳腺癌细胞株中的作用机制；以及4)测试先导化合物和最佳类似物抑制乳腺癌生长、抑制乳腺癌体内转移的能力，并寻找疗效的标志物。意义：我们的最终目标是发现和开发治疗乳腺癌的新的口服活性药物，能够抑制肿瘤细胞的生长和转移。重要的是，非典型的RAMBA既可以抑制内分泌敏感的乳腺癌，也可以抑制内分泌抵抗(内分泌治疗无效)乳腺癌，还可以对抗子宫增生，这与选择性雌激素受体调节剂(SERM)不同，如他莫昔芬和芳香酶抑制剂(AIs)。拟议的研究如果成功进行，将确定至少一到两种高度优化的、口服有效的非典型RAMBA，适用于乳腺癌治疗的高级临床前开发。这些研究还将导致识别将在临床试验中有用的生物标记物。

项目成果

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

• DOI: 10.1007/s00280-012-1877-z
• 发表时间: 2012-08
• 期刊: CANCER CHEMOTHERAPY AND PHARMACOLOGY
• 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.

Anti-tumor effects of a novel retinoic acid metabolism blocking agent VN/14-1 in the N-methyl-N-nitrosourea-induced rat mammary carcinoma model and its effects on the uterus.

• DOI: 10.1007/s10549-011-1724-7
• 发表时间: 2012-05
• 期刊: BREAST CANCER RESEARCH AND TREATMENT
• 影响因子: 3.8
• 作者: Goss, Paul E.;Qi, Shangle;Hu, Haiqing;Gediya, Lalji K.;Purushottamachar, Puranik;Godbole, Abhijit M.;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.

• DOI: 10.1016/j.steroids.2012.09.003
• 发表时间: 2012-12
• 期刊: Steroids
• 影响因子: 2.7
• 作者: Purushottamachar P;Njar VC
• 通讯作者: Njar VC

First MNKs degrading agents block phosphorylation of eIF4E, induce apoptosis, inhibit cell growth, migration and invasion in triple negative and Her2-overexpressing breast cancer cell lines.

首先，MNK降解药物阻断EIF4E的磷酸化，诱导细胞凋亡，抑制细胞的生长，迁移和侵袭三重阴性和HER2过表达的乳腺癌细胞系。

• DOI: 10.18632/oncotarget.1528
• 发表时间: 2014-01-30
• 期刊: Oncotarget
• 作者: Ramalingam S;Gediya L;Kwegyir-Afful AK;Ramamurthy VP;Purushottamachar P;Mbatia H;Njar VC
• 通讯作者: Njar VC

Simultaneous targeting of androgen receptor (AR) and MAPK-interacting kinases (MNKs) by novel retinamides inhibits growth of human prostate cancer cell lines.

• DOI: 10.18632/oncotarget.3084
• 发表时间: 2015-02-20
• 期刊: Oncotarget
• 作者: Ramamurthy VP;Ramalingam S;Gediya L;Kwegyir-Afful AK;Njar VC
• 通讯作者: Njar VC