Project 2: Specifically Targeting Oncoproteins with PCC Agent-Loaded Nanoparticles: KRASG12D and AktE17K

项目2：用PCC载药纳米颗粒特异性靶向癌蛋白：KRASG 12 D AktE17K。 摘要： 癌基因中的激活点突变通常是癌症驱动突变。常见的例子包括 当在密码子12、13或61处突变时，RAS家族[1]。Akt的E17 K突变[2]，加上 表皮生长因子受体（EGFR）[3]或磷脂酰肌醇3-激酶（PI 3 k）[4]是其它实例。 对这些癌蛋白具有选择性的试剂可以作为体外（组织染色）工具，或潜在地作为药物 只针对疾病相关的突变体，从而避免了抑制 野生型（wt）变体[5]存在于健康组织中。例如，EGFR抑制剂CO-1686 （目前在试验中[6]）对与一些非小细胞肺癌相关的T790 M突变具有特异性， 并且被设计为最小化当靶向wt EGFR时可能出现的毒性（例如皮疹）[7]。 然而，激活突变通常不与结合口袋相关，这是小分子的需要。 分子抑制剂开发。单克隆抗体（mAb）可以针对突变的癌蛋白，[8- 10]。 10]但单克隆抗体不进入通常含有癌蛋白的活细胞[11，12]。我们建议建立在 三种Caltech技术：表位靶向蛋白质催化捕获（PCC）剂（Heath）[13，14]， 聚环糊精纳米颗粒（NP）递送系统（Davis）[15]和蛋白水解靶向嵌合分子 （protacs）[16]（Deshaies），开发一种选择性检测和药物突变癌蛋白的方法。 NSBCC主题的基本原理：癌蛋白特异性药物作为联合治疗带来的独特价值 [17，18]的一个重要方面是，它们应该显著打开药物组合的治疗窗口。

PROJECT 2: Specifically Targeting Oncoproteins with PCC Agent-Loaded Nanoparticles: KRASG12D and AktE17K. ABSTRACT: Activating point mutations in oncogenes are often cancer driver mutations. Common examples include the RAS family when mutated at codons 12, 13, or 61[1]. The E17K mutation of Akt [2], plus mutations in the epidermal growth factor receptor (EGFR)[3], or Phosphatidylinositol 3-kinases (PI3k)[4] are other examples. Reagents selective for such oncoproteins can serve as in vitro (tissue staining) tools, or potentially as drugs that target only the disease-associated mutant, thus avoiding the toxic side-effects that stem from inhibition of the wild-type (wt) variants [5] that reside in healthy tissues. For example, the EGFR inhibitor CO-1686 (currently in trials[6]) is specific for the T790M mutation associated with some non-small cell lung carcinomas, and is designed to minimize toxicities (such as skin rash) that can appear when wt EGFR is targeted[7]. However, activating mutations are often not associated with a binding pocket, which is a requirement for small molecule inhibitor development. Monoclonal antibodies (mAbs) can be raised against mutant oncoproteins,[8- 10] but mAbs do not enter the living cells that often harbor the oncoproteins[11, 12]. We propose to build upon three Caltech technologies: epitope targeted Protein Catalyzed Capture (PCC) Agents (Heath)[13, 14], polycyclodextrin nanoparticle (NP) delivery systems (Davis)[15], and proteolysis-targeting chimeric molecules (protacs)[16] (Deshaies), to develop an approach for selectively detecting and drugging mutant oncoproteins. Rationale with NSBCC theme A unique value brought by oncoprotein specific drugs as combination therapy components[17, 18] is that they should significantly open up the therapeutic window for drug combinations.