Abstract

Antibody Drug Conjugates (ADCs) are a class of therapeutic agents that treat cancer by delivering potent payloads to tumor cells in an antigen-dependent manner. All current FDA-approved ADC’s deliver potent cytotoxins to tumor cells, thereby resulting in tumor regression. Building on this success, our lab’s goal is to develop ADC’s that deliver Toll-like receptor (TLR) agonists to target specific tumor-associated immune cells TLR-receptor expressing immune cells. The end result of the TLR agonists is to stimulate the patient’s own immune system which, in turn attacks the tumor cells. The research described herein will focus specifically on a compound known as E104, a potent TLR-7 agonist recently identified by our lab. The goal of this study is to synthesize and evaluate analogs that may offer improved potency over E104 in order to build on our success with this molecule. These designed analogs were based around changing identity and the placement of substituents on the terminal benzyl ring. In order to prepare these analogs, we have developed a 7-step synthetic route of several analogs that was based off the previously reported synthesis of E104. Several obstacles were encountered during the execution of this synthetic route resulting in changes in the reaction conditions in order to minimize byproducts and maximize the yield. The activity of these compounds was evaluated in B-cell reporter assays. It was found that both analogs were agonists of TLR7, but neither was found to be more potent than E104.