DISCOVERY OF PEPTIDE ANTICANCER DRUGS

我们提出的这一NCDDG合作协议的长期目标是 鉴定和开发具有主要抗肿瘤活性合成肽 针对常见的和通常难治的癌症形式，包括 乳腺、前列腺、肺、结肠和黑色素瘤， 白血病和淋巴瘤。 这一建议的科学依据是一个新的 “突破性”技术，快速生产和筛选大型 由数百万个合成肽组成的文库， 一种随机合成技术，它产生单肽实体， 单个固相珠粒。 产生这种库的能力 已经与快速技术结合起来，用两个 互补战略。 第一种技术涉及直接分子 探测癌症相关受体，如表皮生长因子 因子受体和p185 HER 2/neu。 第二种技术使用库 专门设计用于在溶液中测试肽， 相关的人类癌细胞系。 用于生产的合成程序 这些库是非常通用的，允许将D以及 L氨基酸或其他设计氨基酸，并允许产生 具有定义的构象约束的文库，包括环状 缩氨酸 一旦识别出与天然配体结合的肽， 癌症相关受体中的受体位点，或选择性抑制 肿瘤细胞的体外生长，相关肽对“活性 将对“珠”进行测序并重新合成结合亲和力， 生物化学和生物学研究。 利用分子建模和肽 构象和地形约束技术，药物引线将 转化为具有良好药代动力学的候选肽类药物 特性. 然后在体外和体内测试候选药物。 体内肿瘤系统与相关的人肿瘤（例如，在SCID小鼠中）。 活性化合物也将在离散的基础上提供给NCI， 通过筛选程序进行测试。 我们方法的可行性 已经在最初的实验中建立，其中文库 已经合成了至少250万种肽， 从活性珠中分离出的单个肽与癌症有关， 受体结合活性或抑制癌细胞生长。 我们 因此，我们相信，发现新的抗肿瘤药物的潜力 由科学团队组装的这种方法的代理商是非常 很有希望

Our long-range objective of this proposed NCDDG Cooperative Agreement is to identify and develop synthetic peptides which have major antitumor activity against common and often refractory forms of cancer including cancers of the breast, prostate, lung, colon, and melanoma, and drug-resistant leukemias and lymphomas. The scientific basis for this proposal is a new "breakthrough" technology for rapidly producing and screening large libraries comprised of millions of synthetic peptides produced via a novel random synthesis technique which produces single peptide entities on individual solid phase beads. This capability to produce such libraries has been coupled to rapid techniques to screen the libraries with two complementary strategies. The first technique involves direct molecular probing against cancer-associated receptors such as the Epidermal Growth Factor Receptor, and p185 HER2/neu. The second technique employs libraries specially designed to permit peptides to be tested in solution against relevant human cancer cell lines. The synthetic procedures used to produce the libraries are very versatile and permit incorporation of D as well as L amino acids, or other designer amino acids, and permit the creation of libraries with defined conformational constraints including cyclic peptides. Once peptides are identified which bind to the natural ligand acceptor site in cancer-associated receptors, or which selectively inhibit the in vitro growth of tumor cells, the relevant peptides on the "active beads" will be sequenced and resynthesized for binding affinity, biochemical and biologic studies. Using molecular modeling and peptide conformational and topographical constraining techniques, drug leads will be converted into candidate peptide drugs with favorable pharmacokinetic properties. The candidate drugs are then tested in both in vitro and in vivo tumor systems with the relevant human tumor (e.g. in SCID mice). Active compounds will also be provided to the NCI on a discrete basis for testing through its screening program. The feasibility of our approach has already been established in initial experiments wherein libraries containing at least 2.5 million peptides have been synthesized and from which individual peptides from active beads have been isolated with cancer- receptor binding activity, or inhibition of cancer cell growth. We therefore believe that the potential for discovery of major new anti-tumor agents with this approach by the scientific team assembled is extremely promising.