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.

描述（由申请方提供）：念珠藻素是一类结构多样的聚酮化合物/非核糖体肽天然产物，具有强效抗癌活性。然而，尽管有这种令人印象深刻的活性，但念珠藻素发展为有益的癌症化疗剂已经遭受了与治疗相关的临床上显著的神经毒性。尽管如此，这种天然产品有前途的治疗谱激励了Acera Biosciences Inc.。去寻找和开发一种可以重新进入临床评估的念珠藻素化合物。在这项发现工作中，该公司寻求生成大型的，结构多样的念珠藻素化合物库，用于随后的生物活性筛选。由于念珠藻素天然产物的复杂化学结构，其特征在于多个立体中心、大环内酯环和反应性2-环氧化物部分，通过传统合成方法产生这些化合物需要多个步骤，导致总产率低和每个化合物的成本高。因此，这些方法不适于快速生产结构多样的化合物。因此，在第一阶段的STTR提案中，Acera将开发一种新型的高通量合成技术，该技术将能够获得多种念珠藻素类似物，这些类似物可以快速筛选出所需的药理学特性。这个创新的合成平台旨在利用常规固相合成来构建含有线性念珠藻素中间体的化合物库。所提出的策略的特点涉及化学酶转化成成熟的，大环念珠藻素类似物的线性念珠藻素中间体。特别地，Acera Biosciences Inc.试图利用念珠藻素硫酯酶（Crp TE）和念珠藻素环氧酶（CrpE）的催化能力，以特异性地和有效地将树脂结合的中间体转化为带有关键环氧官能团的大环化合物。为了建立这种方法的可行性，这项拟议的研究旨在通过与18个市售苯丙氨酸类似物取代，将结构多样性纳入3-氯-O-甲基-酪氨酸念珠藻素合成子。将使用在亨利福特健康系统开发的多方面临床前药物开发范例筛选所得的18种新型念珠藻素化合物的抗肿瘤活性和神经毒性。该策略的一个关键特征是需要少量的化合物来鉴定初始先导化合物，使其成为念珠藻素类似物的高通量化学酶促生产的理想补充。一旦概念验证建立，第二阶段的研究工作将应用该技术产生数千种化学上不同的念珠藻素化合物，这些化合物将被筛选出所需的药理活性。确定的先导化合物可以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。 公共卫生关系：癌症代表了一个重大的全球人类健康问题，证明了大量的研究投资，发现和开发新的治疗方法。隐藻素是一种已知的、有效的抗癌化合物，由于无法忍受的副作用而从临床试验中退出。这项拟议的研究旨在开发一种新技术，用于快速生成可能显示较少副作用的念珠藻素类似物，从而使医生能够在与这种通常致命的疾病的斗争中利用念珠藻素。