Synthesis of hetero-trifunctional cross linkers for the design and evaluation of antibody-mediated delivery of chimeric protein degraders

这项提议寻求开发基于PROTACs(以嵌合体为靶标的蛋白质分解)的新抗体结合物。这项工作代表了一种新的靶向癌症的范例，涉及到使用小分子PROTAC结合物，它包括一种靶向剂，它可以结合到癌基因或其他生长必需蛋白和脑布隆(一种邻苯二甲胺类似物)上。在这种情况下，目标降解的蛋白质(S)是溴域，它参与组蛋白的加工，从而参与细胞的生长。我们的新概念是生成包含PROTAC的抗体-PROTAC结合物，以进一步增强抗体和PROTAC的治疗效果。因此，该项目将包括合成新的抗体-PROTAC结合物。具体地说，我们将研究和优化具有适当间距和自杀性的连接体的合成，以便这些连接体将作为有效的有效载荷与抗体进行适当的结合。作为概念验证，我们将使用赫赛汀，它具有几个关键优势，包括作为临床验证的抗体高度有用，以衡量临床成功，以及提供操作的自由，因为它是非专利的。几个连接子以及两个不同的PROTAC被提出来提供这一概念证明的重要验证。在这里，Perrin实验室将与Iprogen合作产生这些新的抗体-PROTAC用于评估。为了获得成功，Perrin实验室已经通过之前的NSERC Engage赠款和MITACS赠款支持了与其工业合作伙伴Iprogen的合作研究。

This proposal seeks to develop new Antibody conjugates based on PROTACs (proteolysis targeting chimeras). This work represents a novel paradigm for targeting cancer and involves the use of a small molecule PROTAC conjugate, which comprises a targeting agent that can bind to an oncogene or other growth-essential protein and cereblon, a phthalidomide analog. In this case the protein(s) targeted for degradation are bromodomains, which are involved in histone processing and thus cell growth. Our novel concept is to generate an antibody-PROTAC conjugates that comprise the PROTAC so as to further potentiate as well as increase therapeutic efficacy of both the antibody and the PROTAC. Hence this project will comprise the synthesis of new antibody-PROTAC conjugates. Specifically, we will investigate and optimize the synthesis of linkers with appropriate spacing as well as immolative properties such that these will serve as potent payloads for suitable conjugation to antibodies. As proof-of-concept, we will use Herceptin which has several key advantages including being highly useful as a clinically validated antibody for gauging clinical success as well as providing freedom to operate as it is off-patent. Several linkers as well as two different PROTACs are proposed to provide important validation of this proof of concept.Here the Perrin lab will partner with Iprogen to generate these new antibody-PROTACs for evaluation.Auguring for success, the Perrin lab has already supported collaborative research with its industrial partner Iprogen through a previous NSERC engage grant and a MITACS grant.