Abstract
Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives of paclitaxel designed to bind to this intermediate site differentially depending on the isotype of β-tubulin. Since β-tubulin isotypes have tissue-dependent expression—specifically, the βIII isotype is very abundant in aggressive tumors and much less common in normal tissues—this is expected to lead to tubulin targeted drugs that are more efficacious and have less side effects. Seven derivatives of paclitaxel were designed and four of these were amenable for synthesis in sufficient purity and yield for further testing in breast cancer model cell lines. None of the derivatives studied were superior to currently used taxanes, however computer simulations provided insights into the activity of the derivatives. Our results suggest that neither binding to the intermediate binding site nor the final binding site is sufficient to explain the activities of the derivative taxanes studied. These findings highlight the need to iteratively improve on the design of taxanes based on their activity in model systems. Knowledge gained on the ability of the engineered drugs to bind to targets and bring about activity in a predictable manner is a step towards personalizing therapies.
Highlights
The taxanes, including paclitaxel and docetaxel, target tubulin, the subunit protein of microtubules, and bind to a well-characterized site on β-tubulin [1]
Breast cancer tumors are characterized in terms of their expression of various cell surface receptors such as HER2, estrogen receptor (ER) and progesterone receptor (PR), which are involved in cell signaling and cellular proliferation
These experiments used affinity-purified βII and βIII tubulin isotypes from a bovine brain source; the α-tubulin was a mixture of isotypes; these forms of tubulin are referred to as αβII and αβIII, respectively
Summary
The taxanes, including paclitaxel and docetaxel, target tubulin, the subunit protein of microtubules, and bind to a well-characterized site on β-tubulin [1]. The mechanisms of binding and action, are highly complex. Unlike other anti-tubulin drugs, the taxanes target the intact microtubule and their binding site is in the microtubule lumen [2]. Complex Mechanisms of Action of Novel Taxanes work by Freedman et al [2] mapped the nanopores along the microtubule surface through which taxanes need to pass in order to reach the binding site. Our goal was to rationally design and test novel taxane derivatives that would bind to the intermediate binding site with differential affinity depending on the β-tubulin isotype expressed in cells
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