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

项目2：用PCC试剂载药纳米粒特异性靶向癌蛋白：KrasG12D 和AktE17K。 摘要： 激活癌基因中的点突变通常是癌症驱动的突变。常见的示例包括 RAS家族在密码子12、13或61处突变[1]。Akt[2]的E17K突变，加上 另外一些例子是表皮生长因子受体(EGFR)[3]，或磷脂酰肌醇3-激酶(PI3K)[4]。 对这些癌蛋白有选择性的试剂可用作体外(组织染色)工具，或潜在地用作药物 这只针对与疾病相关的突变体，从而避免了由于抑制 存在于健康组织中的野生型(Wt)变体[5]。例如，EGFR抑制剂CO-1686 (目前处于试验[6]中)针对与某些非小细胞肺癌相关的T790M突变， 旨在将wt EGFR靶向时可能出现的毒性(如皮疹)降至最低[7]。 然而，激活突变通常与结合口袋无关，这是小分子 分子抑制剂的开发。可以针对突变的癌蛋白[8-]产生单抗。 但单抗不会进入通常含有癌蛋白的活细胞[11，12]。我们计划在此基础上 加州理工学院的三项技术：表位靶向蛋白催化捕获(PCC)试剂(Heath)[13，14]， 聚环糊精纳米粒(NP)递送系统(Davis)[15]，以及以蛋白质分解为靶向的嵌合分子 (PROTACS)[16](Deshaies)，以开发一种选择性检测和给突变癌蛋白下药的方法。 NSBCC主题的理论基础癌蛋白特异性药物作为联合治疗带来的独特价值 组分[17，18]是它们应该显著地为药物组合打开治疗窗口。

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.