Design of Small Molecule Antagonists of EGF-EGFR Binding

描述（由申请人提供）：表皮生长因子（EGF）受体是一种参与多种癌症的细胞表面受体。 用小分子抑制其细胞内激酶结构域最近已被证明具有临床疗效。 我们提出了一种新的方法来阻断激活的EGF受体使用小分子结合到细胞外结构域，从而减弱信号的EGF在早期干预点-一个，重要的是，不需要细胞渗透的药物。 小分子将被设计成模拟EGF分子表面上关键暴露的受体结合残基，使得它们能够与天然配体EGF竞争结合受体。 为了探索EGF的“生物活性”构象，将使用分子动力学模拟沿着使用NMR确定的结构生成EGF的结构系综。 动态药效团将从系综中导出，并用于小分子数据库的虚拟屏幕中。 该项目的第一阶段包括以下目标：1）生成EGF的3-D动态模型，2）鉴定参与配体-受体结合以生成药效团模板的表面氨酰基侧链，3）鉴定与模板匹配的非肽化学物质，以及4）评价所选化合物的生物化学和药理学活性。 阶段I的目标是鉴定1-20微摩尔范围内的拮抗剂活性。 第一阶段的成功将导致第二阶段的初步线索细化为EGF受体拮抗剂的临床前候选药物。 拟定商业应用： 癌症是威胁所有年龄段人类生命的主要死亡原因。 EGF受体的异常表达已在许多癌症中观察到，包括脑癌、头颈癌、乳腺癌、肺癌和膀胱癌，并且是恶性过程的主要原因。 通过一种新的细胞外相互作用机制发挥作用的拮抗剂将被开发用于潜在的临床用途，并将提供更高的疗效和更低的毒性的前景。

DESCRIPTION (provided by applicant): Epidermal growth factor (EGF) receptor is a cell surface receptor involved in a number of cancers. Inhibition of its intracellular kinase domain with small molecules has recently been proven to have clinical efficacy. We propose a novel approach to block activation of the EGF receptor using small molecules that bind to the extracellular domain, thus attenuating the signaling of EGF at an earlier intervention point - one that, importantly, does not require cell penetration by drug. Small molecules will be designed to mimic the critical exposed receptor-binding residues on the EGF molelcular surface, so that they are able to bind to the receptor in competition with the natural ligand EGF. In order to explore the "bioactive" conformations of EGF, an ensemble of structures of EGF will be generated using molecular dynamics simulation along with structures determined using NMR. Dynamic pharmacophores will be derived from the ensemble and used in a virtual screen of a small molecule database. Phase I of this project includes the following objectives: 1) generation of a 3-D dynamic model of EGF, 2) identification of surface aminoacyl side chains which participate in ligand-receptor binding to generate pharmacophore templates, 3) identification of non-peptide chemicals that match the template, and 4) evaluation of biochemical and pharmacological activities of the selected compounds. The goal of Phase I is to identify antagonist activity in the range of 1-20 micromolar. The success of Phase I will lead to Phase II refinement of the initial leads into pre-clinical candidates for EGF receptor antagonism. PROPOSED COMMERCIAL APPLICATION: Cancer is a major cause of death threatening human lives at all ages. Aberrant expression of the EGF receptor has been observed in many cancers including those of the brain, head and neck, breast, lung and bladder, and is a major cause of the malignant processes. Antagonists acting through a novel extracellular interaction mechanism will be developed for potential clinical use and will offer the prospects of higher efficacy and lower toxicity.