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

本提案旨在开发基于PROTACs（蛋白水解靶向嵌合体）的新抗体偶联物。这项工作代表了一种靶向癌症的新范例，涉及使用小分子PROTAC偶联物，它包含一种靶向剂，可以结合癌基因或其他生长必需蛋白和小脑，酞度胺类似物。在这种情况下，降解的目标蛋白是溴结构域，它参与组蛋白加工，从而参与细胞生长。我们的新概念是产生一种包含PROTAC的抗体-PROTAC偶联物，从而进一步增强抗体和PROTAC的治疗效果。因此，该项目将包括合成新的抗体- protac偶联物。具体地说，我们将研究和优化具有适当间距的连接体的合成，以及自燃特性，使这些连接体能够作为有效载荷与抗体结合。作为概念验证，我们将使用赫赛汀，它有几个关键优势，包括作为一种临床验证抗体非常有用，可以衡量临床成功，并提供非专利操作的自由。提出了几个链接器以及两个不同的protac，以提供对该概念证明的重要验证。在这里，Perrin实验室将与Iprogen合作生产这些新的抗体- protacs进行评估。为了取得成功，Perrin实验室已经通过之前的NSERC参与资助和MITACS资助，支持与其工业合作伙伴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.