posted on 2019-05-13, 00:00authored byRay R. Zhang, Joseph J. Grudzinksi, Tej I. Mehta, Ronald R. Burnette, Reinier Hernandez, Paul A. Clark, Jonathan A. Lubin, Anatoly N. Pinchuk, Justin Jeffrey, Marc Longino, John S. Kuo, Jamey P. Weichert
Alkylphosphocholine
(APC) analogs are a novel class of broad-spectrum
tumor-targeting agents that can be used for both diagnosis and treatment
of cancer. The potential for clinical translation for APC analogs
will strongly depend on their pharmacokinetic (PK) profiles. The aim
of this work was to understand how the chemical structures of various
APC analogs impact binding and PK. To achieve this aim, we performed in silico docking analysis, in vitro and in vivo partitioning
experiments, and in vivo PK studies. Our results
have identified 7 potential high-affinity binding sites of these compounds
on human serum albumin (HSA) and suggest that the size of the functional
group directly influences the albumin binding, partitioning, and PK.
Namely, the bulkier the functional groups, the weaker the agent binds
to albumin, the more the agent partitions onto lipoproteins, and the
less time the agent spends in circulation. The results of these experiments
provide novel molecular insights into the binding, partitioning, and
PK of this class of compounds and similar molecules as well as suggest
pharmacological strategies to alter their PK profiles. Importantly,
our methodology may provide a way to design better drugs by better
characterizing the PK profile for lead compound optimization.