A chemoenzymatic technology for the efficient synthesis of novel cryptophycins

高效合成新型隐藻素的化学酶技术

• 批准号: 7668904
• 负责人: DAVID H SHERMAN
• 金额: $ 32.27万
• 依托单位: ALLUVIUM BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-11 至 2011-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668904
• 关键词: Accounting; Adverse effects; American Cancer Society; Anabolism; Antineoplastic Agents; Area; Binding; Biological; Biological Factors; Biotechnology; Cause of Death; Cessation of life; Chemical Structure; Chemicals; Collaborations; Colon; Complement; Complex; Coupled; Cryptophycin; Cryptophycin 52; Cyanobacterium; Development; Diagnosis; Disease; Drops; Drug Formulations; Drug Kinetics; Enzymes; Epoxy Compounds; Evaluation; Feasibility Studies; Future; Generations; Health; Health system; Heart Diseases; Human; In Vitro; Investigation; Investments; Knowledge; Lead; Libraries; Licensing; Macrocyclic Compounds; Malignant Neoplasms; Methods; Michigan; Modeling; Parents; Peptides; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Physicians; Plant Resins; Preclinical Drug Development; Production; Program Development; Property; Prostate; Recombinants; Relative (related person); Research; S Phase; Screening procedure; Series; Small Business Technology Transfer Research; Solid; Solid Neoplasm; Solubility; Solutions; Specificity; Staging; System; Technology; Testing; Therapeutic; Therapy Clinical Trials; Time; Tyrosine; Universities; Work; analog; anti-cancer therapeutic; anticancer activity; base; cancer prevention; chemotherapeutic agent; clinically significant; comparative; cost; cost effective; cryptophycin 1; cytotoxic; drug development; drug discovery; drug production; epoxidase; follow-up; functional group; in vivo; innovation; innovative technologies; interest; method development; neurotoxic; neurotoxicity; new technology; next generation; novel; phenylalanine analog; pre-clinical; preclinical evaluation; programs; public health relevance; research clinical testing; success; tumor

DESCRIPTION (provided by applicant): The cryptophycins are a structurally diverse class of polyketide/non-ribosomal peptide natural products that possess potent anticancer activity. However, despite this impressive activity, the development of the cryptophycins into a beneficial cancer chemotherapeutic agent has suffered from clinically significant neurotoxicity that correlates with treatment. Nonetheless, the promising therapeutic spectrum of this natural product has motivated Acera Biosciences Inc. to pursue the discovery and development of a cryptophycin compound that that can re-enter clinical evaluation. Within this discovery effort, the company seeks to generate large, structurally diverse libraries of cryptophycin compounds for subsequent biological activity screening. Due to the complex chemical structure of the cryptophycin natural products, which features multiple stereocenters, a macrolactone ring, and a reactive 2-epoxide moiety, the generation of these compounds by traditional synthetic methods requires multiple steps, resulting in low overall yields and a high cost per compound. As such, these methods are not amenable to the rapid production of structurally diverse compounds. Accordingly, in this Phase I STTR proposal, Acera will develop a novel high throughput synthetic technology that will enable access to a diversity of cryptophycin analogues that can be rapidly screened for desirable pharmacological properties. This innovative synthetic platform seeks to utilize routine solid-phase synthesis for the construction of compound libraries containing linear cryptophycin intermediates. The hallmark of the proposed strategy involves chemoenzymatic transformation of the linear cryptophycin intermediates into mature, macrocyclic cryptophycin analogues. In particular, Acera Biosciences Inc. seeks to leverage the catalytic power of the cryptophycin thioesterase (Crp TE) and the cryptophycin epoxidase (CrpE) to specifically and efficiently transform the resin-bound intermediates to macrocyclic compounds bearing the key epoxide functional group. To establish the feasibility of this approach, this proposed research aims to incorporate structural diversity into the 3-chloro-O-methyl-tyrosyl cryptophycin synthon via substitution with 18 commercially available phenylalanine analogues. The resulting 18 novel cryptophycin compounds will be screened for anti-tumor activity and neurotoxicity using a multi-faceted preclinical drug development paradigm developed at Henry Ford Health System. A key feature of this strategy is that small quantities of compounds are required to identify an initial lead compound, making it an ideal complement to the high throughput chemoenzymatic production of cryptophycin analogues. Once proof-of-concept is established, research efforts in Phase II will apply this technology toward the generation of thousands of chemically diverse cryptophycin compounds that will be screened for desirable pharmacological activity. Identified lead compounds can then be licensed to pharmaceutical or biotechnology companies interested in expanding their anti-cancer development programs. PUBLIC HEALTH RELEVANCE: Cancer represents a significant global human health concern that justifies substantial research investments for the discovery and development of novel treatments. Cryptophycin is a known, potent anti-cancer compound that has been dropped from clinical testing due to intolerable side-effects. This proposed research seeks to develop a novel technology for the rapid generation of cryptophycin analogues that may display fewer side effects, thereby enabling cryptophycin to be utilized by physicians in the battle against this often deadly disease.

说明(申请人提供)：隐膜蛋白是一类结构多样的聚酮/非核糖体多肽天然产物，具有强大的抗癌活性。然而，尽管具有这种令人印象深刻的活性，但隐孔蛋白发展成为一种有益的癌症化疗药物的过程中，受到了与治疗相关的临床显著神经毒性的影响。尽管如此，这种天然产品的前景看好的治疗光谱促使Acera生物科学公司寻求发现和开发一种可以重新进入临床评估的隐霉素化合物。在这项发现工作中，该公司寻求产生大型的、结构多样化的隐霉素化合物文库，用于后续的生物活性筛选。由于隐孢子素天然产物的化学结构复杂，具有多个立体中心、一个大内酯环和一个活性的2-环氧化物部分，传统的合成方法需要多个步骤才能合成这些化合物，导致总收率低和每种化合物的成本较高。因此，这些方法不适用于结构多样的化合物的快速生产。因此，在这项第一阶段的STTR提案中，Acera将开发一种新的高通量合成技术，该技术将使人们能够获得各种隐孢霉素类似物，这些类似物可以快速筛选出所需的药理特性。这个创新的合成平台寻求利用常规的固相合成来构建包含线性隐霉素中间体的化合物文库。所提出的策略的特点是将线性隐霉素中间体通过化学酶转化为成熟的大环隐霉素类似物。特别是，Acera Biosciences Inc.寻求利用隐孢子素硫酯酶(CRP TE)和隐孢子素环氧酶(CRPE)的催化能力，将树脂结合的中间体有效地转化为具有关键环氧化物官能团的大环化合物。为了确定这种方法的可行性，这项拟议的研究旨在通过用18个商业上可用的苯丙氨酸类似物来取代3-氯-O-甲基-酪氨基隐孢子素合成子来引入结构多样性。由此产生的18种新型隐霉素化合物将使用亨利·福特健康系统开发的多方面临床前药物开发范例来筛选抗肿瘤活性和神经毒性。这一策略的一个主要特点是需要少量的化合物来鉴定初始的先导化合物，使其成为高通量化学酶法生产隐霉素类似物的理想补充。一旦概念验证建立，第二阶段的研究工作将把这项技术应用于产生数千种化学上不同的隐霉素化合物，这些化合物将被筛选出理想的药理活性。然后，已识别的先导化合物可以被授权给有兴趣扩大其抗癌开发计划的制药或生物技术公司。 公共卫生相关性：癌症是一个重要的全球人类健康问题，值得为发现和开发新的治疗方法而进行大量研究投资。隐孢子素是一种已知的、有效的抗癌化合物，由于无法忍受的副作用，已被临床试验淘汰。这项拟议的研究旨在开发一种新的技术，以快速产生可能显示出较少副作用的隐霉素类似物，从而使医生能够利用隐孢子素来对抗这种通常是致命的疾病。