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

点击翻译按钮获取中文摘要

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.