ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is a devastating and intractable type of cancer. Current antineoplastic drugs do not improve the median survival of patients diagnosed with GBM beyond 14–15 months in part because the blood-brain barrier is generally impermeable to many therapeutic agents. Drugs that target microtubules (MT) have shown remarkable efficacy in a variety of cancers, yet their use as GBM treatments has also been hindered by the scarcity of brain-penetrant MT-targeting compounds. We have discovered a new alkylindole compound, ST-11, that acts directly on MTs and rapidly attenuates their rate of assembly. Accordingly, ST-11 arrests GBM cells in prometaphase and triggers apoptosis. In vivo analyses reveal that unlike current antitubulin agents, ST-11 readily crosses the blood-brain barrier. Further investigation in a syngeneic orthotopic mouse model of GBM shows that ST-11 activates caspase-3 in tumors to reduce tumor volume without overt toxicity. Thus, ST-11 represents the first member of a new class of brain-penetrant antitubulin therapeutic agents.

Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

“…Under these experimental conditions, 8, 20 and 27 exhibited IC 50 s of 1.4, 0.9 and 1.6 μM, respectively, and 23 was inactive at concentrations up to 20 μM (Table 4). To build on these results, we measured the ability of modified carbazoles to influence the partitioning of MT dimers and polymers, an index of MT assembly and disassembly as previously described [14]. In this assay, compounds are incubated with sheared MTs at 37°C and the resulting amounts of tubulin dimers (free tubulin) and polymer (MT) after 15 min is measured on polyacrylamide gels [30].…”

“…WST-1 (Roche, Pleasanton, CA) was used to evaluate cell viability as described [14] 72 h following drug treatment according to the manufacturer's protocol. Maximal killing activity was identified as the maximal % reduction in cell viability measured at drug concentrations tested.…”

“…Three of the most extensively studied classes of MTAs are vinca alkaloids, taxanes and colchicinoids, which bind to distinct sites on tubulin and differentially affect MT dynamics [1,12]. Prototypical MTAs that bind to the colchicine sites include combretastatin A-4 (1), the carbazole-based analogues of combretastatin (2) that weakly inhibit tubulin polymerization and yet triggers pronounced apoptosis, and nocodazole (3), which rapidly and fully inhibits tubulin polymerization and triggers apoptosis in cancer cells (Figure 1) [13,14].…”

“…In a previous study, we identified a series of indole-based MTAs that bind to the colchicine site of tubulin, reduce MT polymerization in vitro, reduce MT dynamics in GBM cell lines in culture and kill GBM cells by apoptosis when tested in an orthotopic syngeneic mouse model [14]. Here, we used these results as the starting point for the development of a series of carbazole-based MTAs (4) and studied their antitumor activity in both GBM cell lines and patient-derived GBM cells in culture.…”

6-MOMIPP, a novel brain-penetrant anti-mitotic indolyl-chalcone, inhibits glioblastoma growth and viability

“…Most importantly, there was a striking parallel between plasma and brain concentrations of 6-MOMIPP at all time points, strongly suggesting that the compound freely penetrates the BBB. With one recent exception (ST-11) [69], most MTAs exhibit poor passage across the BBB, limiting their effectiveness for treating primary or secondary brain tumors. Thus, 6-MOMIPP may have potential advantages over the currently available microtubuledestabilizing agents for treatment of brain malignances.…”