Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

Abstract

(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide.

Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities

“…Together, these data demonstrate that, although a diverse array of C-6 taccalonolide modifications can alter target engagement and cellular potency, these modifications do not alter the overall mechanism of action of these compounds as microtubule stabilizers that promote persistent cellular effects due to their irreversible target engagement. This is consistent with previous reports demonstrating that the addition of this paclitaxel side chain onto the discodermolide backbone resulted in compounds with activity that resembled discodermolide albeit with improved cellular potency. , Additionally, it was found that the analogues in this study impact biochemical and cellular activities in a nonlinear manner, suggesting distinct effects of C-6 modifications on direct target engagement versus binding of the tubulin target in cells due to compound permeability or stability. While these data suggest that the C-6 modifications produced in this study are not likely to have an improved antitumor efficacy as compared to those of other taccalonolides, we propose that the diversity of structural modifications that are permitted as C-6 modifications offers unprecedented access to facilitate tumor targeting and prodrug strategies that may increase the antitumor efficacy of this compound class, which could provide long-term antitumor efficacy, particularly in taxane-resistant settings.…”

“…While this fluorescent taccalonolide probe provided a valuable tool compound to elucidate binding specificity, it did not offer improved cellular potency and is not amenable to further development as a potential therapeutic agent. Previous studies have demonstrated that incorporation of the paclitaxel side chain onto the backbone of other bioactive compounds, including the microtubule stabilizer discodermolide, can alter and even improve their cellular properties. − In the current study, semisynthesis was performed on the taccalonolide skeleton to generate a series of 20 novel taccalonolide analogues designed to enhance the biochemical and cellular potency of this compound class by improving target engagement. The resulting structure–activity relationships of this study have further characterized the optimal taccalonolide binding pocket on tubulin and help refine the modeling of the functional pharmacophore for this unique class of microtubule stabilizing drugs, which will be critical in the design of a therapeutic lead compound of this class.…”

Structural Refinement of the Tubulin Ligand (+)-Discodermolide to Attenuate Chemotherapy-Mediated Senescence

“…Thus, minimizing risk of CIS is an important but underappreciated consideration in anticancer drug development. We have implemented a robust strategy to select molecules that maximize tumor cell death while minimizing CIS based on increasing E Max and AUC and steepening the Hill slope (Fallahi-Sichani et al, 2013;Nadaradjane et al, 2018). This multiparametric approach best maximizes leads for further development, evolving contemporary drug discovery beyond an EC 50 -centric approach and thereby lessening the risk of developing compounds that strongly induce CIS.…”

“…However, despite its promise as anticancer molecule, DDM caused serious interstitial pneumopathy in clinical evaluation (Mita et al, 2004), a condition typically associated with fibrosis and senescence (Jones, 2018). We previously characterized DDM as a potent inducer of chemotherapy-induced senescence (CIS) (Klein et al, 2005;Chao et al, 2011;Nadaradjane et al, 2018), defined as prolonged exit from proliferation that is distinct from quiescence.…”

“…Taxol, unlike DDM, is a comparatively weak inducer of CIS (Klein et al, 2005;Nadaradjane et al, 2018). This is hypothesized to be due to variation in the affinity and pose of binding in the taxol-binding domain of tubulin (Prota et al, 2017), or binding of tubulin ligands to specific tubulin isotypes, or downstream effects thereof.…”