Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy

Abstract

In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor‐targeted glucuronides attractive for translational medicine.

Synthetic Artificial Apoptosis‐Inducing Receptor for On‐Demand Deactivation of Engineered Cells

“…Indeed, activation of the corresponding substrates, glucuronides, in the human body is only associated with diseased tissues such as cancer, and not with normal healthy tissues. [ 25–27 ] Glucuronides are also highly advantageous for receptor design as being highly polar: [ 28–29 ] the use of glucuronic acid as a removable masking group is poised to ensure exofacial localization and accessibility of the trigger to enzymatic activation. As an effector molecule, we used a highly potent intracellular toxin, monomethyl auristatin E (MMAE), which has excellent lipophilicity and cell permeability properties (calculated log P = 3,5).…”

Per‐glycosylation of the Surface‐Accessible Lysines: One‐Pot Aqueous Route to Stabilized Proteins with Native Activity

“…As glycans, we use glucose (Glc) and glucuronic acid (GlcA). We were specifically interested in the latter because small molecule glucuronides are highly polar and water‐soluble [25,26] . We envisioned that glucuronidation can confer these properties to the protein molecules, which can result in a suit of beneficial properties.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–7

“…Zelikin’s group [ 56 ] have reported efficient suppression of tumor growth by enzyme prodrug therapy, which takes advantage of noncovalent albumin binding and, subsequently, delivery of the prodrug to the tumor as well as the endogenous enzymatic repertoire of the tumor. To this end, a total of eight glucuronide prodrugs of highly cytotoxic monomethyl auristatin E (MMAE) were engineered, where a self-immolative scaffold based on o -substituted p -hydroxybenzyl alcohol provided a spacer between the drug, glucuronide, and either the molecular (e.g., alkyne), macromolecular (e.g., PEGs), or supramolecular (e.g., trityl (Tr)-PEG) protraction arm.…”