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

该提案旨在开发基于PROTAC（蛋白水解靶向嵌合体）的新抗体缀合物。这项工作代表了靶向癌症的新范例，涉及使用小分子PROTAC缀合物，其包含可以结合致癌基因或其他生长必需蛋白的靶向剂和cereblon，一种酞胺类似物。在这种情况下，靶向降解的蛋白质是溴结构域，其参与组蛋白加工并因此参与细胞生长。我们的新概念是产生包含PROTAC的抗体-PROTAC缀合物，以便进一步增强以及增加抗体和PROTAC两者的治疗功效。因此，该项目将包括新的抗体-PROTAC缀合物的合成。具体而言，我们将研究和优化具有适当间距以及牺牲性质的接头的合成，使得这些接头将用作与抗体合适缀合的有效有效负载。作为概念验证，我们将使用赫赛汀，赫赛汀具有几个关键优势，包括作为临床验证的抗体非常有用，可用于衡量临床成功，以及提供操作自由，因为它是非专利的。 提出了几种连接体以及两种不同的PROTAC来为这一概念证明提供重要验证。Perrin实验室将与Iprogen合作生产这些新的抗体PROTAC以供评估。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.