Poster: Studies on Conjugates of Hydroxyl-Bearing Payloads: A Silyl Ether Strategy with Potential for Hydrolytic or Assisted Cleavage
Over the course of working on a variety of complex drug conjugate programs within Curia, including antibody drug conjugates (ADCs), diverse ligand-drug conjugates (e.g. PROTACS), and liganded diagnostics (e.g. DOTA) we found that certain high interest drugs were often limited in the choice of a suitable functional group needed to connect the drug to the linker portion of the assemblage. Moreover, program objectives often dictated that the ideal drug conjugate required drug release at the biological site of action by means of cleavable linkers. The amino group is perhaps the most common functional group used to connect drug to linker as exemplified by ADCETRIS®. However, not all drugs of interest possess the requisite amino group necessary for connection. We found this especially true for many natural products, where hydroxyls are a common functional group encountered including poly-hydroxylated substrates. Absent an appropriate functional group on the drug, the only other option is for the drug to be derivatized to provide a suitable functional handle. This approach is normally undesired since the biological profile and likely the safety profile of the drug can change. Considering these challenges, we aimed to explore silicon ethers as a means to expand the arsenal of useful functional handles to both link and subsequently release hydroxyl-bearing drugs, particularly natural products.
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