Hydrophilic Small Molecules That Harness Transthyretin To Enhance the Safety and Efficacy of Targeted Chemotherapeutic Agents

Abstract

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of targeted chemotherapeutic agents while maintaining their hydrophilicity and small size will represent a significant advance toward effective and safe cancer treatment. Here, we present a new approach for enhancing the safety and efficacy of targeted chemotherapeutic agents. By endowing hydrophobic chemotherapeutic agents with a targeting moiety and a hydrophilic small molecule that binds reversibly to the serum protein transthyretin, we generated small hydrophilic drug conjugates that displayed enhanced circulation half-life in rodents and selectivity to cancer cells. To the best of our knowledge, this is the first demonstration of a successful approach that maintains the small size and hydrophilicity of targeted anticancer agents containing hydrophobic payloads while at the same time extending their circulation half-life. This was demonstrated by the superior in vivo efficacy and lower toxicity of our conjugates in xenograft mouse models of metastatic prostate cancer.

Enhancing the Pharmacokinetic Profile of Interleukin 2 through Site-Specific Conjugation to a Selective Small-Molecule Transthyretin Ligand

“…There was no binding affinity of rIL2 to TTR. TLHE ( K d = 516 nM) and TLHE-rIL2 ( K d = 851 nM) displayed binding affinity to TTR that is comparable to the other TLHE conjugates that we have reported earlier , (Figure A). It is important to note that the binding affinity of TLHE-rIL2 is likely underestimated because ∼50% of the TLHE-rIL2 sample is rIL2.…”

“…We have previously developed a series of TLHEs that were used effectively in extending the in vivo half-life of both hydrophilic peptides and hydrophobic anticancer agents. , One of these TLHEs, compound 1 , is a small-molecule TTR ligand that has a linker equipped with a terminal alkyne group (Scheme ). The alkyne group of 1 allowed us to functionalize the linker with a maleimide group, which could potentially be used for conjugation to a cysteine group in rIL2.…”

“…The in silico modeling studies were carried out as previously reported. , The geometry optimization of the TLHE ( 3 ) was carried out at the hybrid density functional B3LYP level with the 6-31G­(d) basis set using the Gaussian 09 program package. To confirm the optimized geometry is at minimum, frequency calculations were carried out on the optimized geometries.…”

Synthesis, Characterization, and Preclinical Evaluation of a Small-Molecule Prostate-Specific Membrane Antigen-Targeted Monomethyl Auristatin E Conjugate

“…TFM1-TFM-3 conjugates contain motifs that reversibly bind to the serum protein transthyretin, thus enhancing the pharmacokinetic profiles of these molecules. 30 In the case of the PSMA-1-vcMMAE conjugate, 31 the PSMA ligand PSMA-1 was used, which previously demonstrated its potential in fluorescent conjugates. 33 In this work, we implemented a synthetic approach to a conjugate based on monomethyl auristatin E, where a previously optimized ligand with a high affinity to PSMA was used as the target molecule.…”

Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects

“…2). AG10 and compound 1 bind to the two thyroxine sites in TTR and do not interfere with the interaction between TTR and holo-RBP 6,28 .…”