Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

Diaz, Philippe; Horne, Eric A.; Xu, Cong; Hamel, Ernest; Wagenbach, Michael; Petrov, Ravil R.; Uhlenbruck, Benjamin; Haas, Brian R.; Hothi, Parvinder; Wordeman, Linda; Gussio, Rick; Stella, Nephi

doi:10.1016/j.ejmech.2018.09.026

Cited by 23 publications

(22 citation statements)

References 39 publications

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“… 12 In previous studies, we developed MDAs (ST-34, ST-360, and ST-377) that bind to the colchicine site of tubulin, inhibit MT assembly, and kill glioma cells in culture (ie, compounds 8, 20, and 27 in ref. 13 ; Figure 1A ). Here we leveraged these results as the starting point to develop a novel chemical entity, ST-401, and studied its MOA and antitumor activity in glioma cells in culture and in the RCAS/tv-a PDGFB-driven glioma mouse model.…”

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confidence: 99%

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Horne

Diaz

Cimino

et al. 2020

Neuro-Oncology Advances

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Background Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. Methods Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. Results We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). Conclusion Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.

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confidence: 99%

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Horne

Diaz

Cimino

et al. 2020

Neuro-Oncology Advances

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“…Recently, a series of carbazole-based MT targeting agents with anti-tumor properties has been reported, confirming the ability of this type of chemical scaffold to interact with the colchicine site of tubulin [28]. The Carba1 scaffold is a versatile one and we are currently synthesizing modified analogs for medicinal chemistry optimization.…”

Section: Discussionmentioning

confidence: 95%

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Peronne

Denarier

Rai

et al. 2020

Preprint

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Phone number +33(0)4 24 76 54 95 71 laurence.lafanechere@univ-grenoble-alpes.fr 25 2 Running title: A new paclitaxel sensitizer that targets tubulin 26 Scientific Research (NWO) CW ECHO grant (711.015.005) to AA. 32 33 The authors declare no potential conflicts of interest 34 35 Word count: 36 Abstract: 158 words 37 Main manuscript, including acknowledgments: 4667 words 38 Figure legends: 1115 words 39 Number of references: 34 40 Abstract 43Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy 44 inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched 45 for drugs which could potentiate its therapeutic effect. We have screened a chemical library 46 3 and selected Carba1, a carbazolone, which exerts synergistic cytotoxic effects on tumor cells 47 grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the 48 colchicine binding-site of tubulin and is a microtubule-destabilizing agent. The Carba1-49 induced modulation of microtubule dynamics increases the accumulation of fluorescent 50 paclitaxel inside microtubules, providing a mechanistic explanation of the observed synergy 51 between Carba1 and paclitaxel. The synergistic effect of Carba1 with paclitaxel on tumor cell 52 viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring 53 paclitaxel accumulation in microtubules can be transposed to in vivo mouse cancer treatments, 54 paving the way for new therapeutic strategies combining low doses of microtubule targeting 55 agents with opposite mechanisms of action. 56 Introduction 57 Microtubules (MTs), dynamic polymeric filaments composed of -tubulin and -tubulin 58 heterodimers, are key components of the cytoskeleton of eukaryotic cells. Their crucial roles 59 in cell division and physiology mainly rely on their ability to rapidly polymerize or 60 depolymerize. Targeted perturbation of this finely tuned process constitutes a major 61 therapeutic strategy. Drugs interfering with MTs are major constituents of chemotherapies for 62 the treatment of carcinomas. A number of compounds bind to the tubulin-MT system. They 63 can be roughly classified into MT-stabilizers such as taxanes or epothilones, and MT-64 destabilizers such as vinca alkaloids, combretastatin and colchicine [1]. It has been 65 demonstrated that binding of vinca alkaloids or colchicine prevents the curved-to-straight 66 conformational change of tubulin at the tip of the growing MT, necessary for proper 67 incorporation of new tubulin dimers into the MT lattice (see reviews [1,2]). 68 Paclitaxel (PTX) binds to the taxane-site of -tubulin and stabilizes the MT lattice by 69 strengthening lateral and/or longitudinal tubulin contacts within the MT [1]. At stoichiometric 70 concentrations, it promotes MT assembly. At low and clinically relevant concentrations, PTX 71

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“…Unlike Carba1, they exert potent killing activities in human glioblastoma cells. A possible explanation for the difference in cytotoxicity observed between Carba1 and the compounds described by Diaz et al [ 24 ] may reside in a lower affinity of Carba1 for the colchicine binding site of the tubulin dimer. Indeed, we found that the affinity of Carba1 for the colchicine site is not very high, in the micromolar range.…”

Section: Discussionmentioning

confidence: 95%

“…Recently, a series of carbazole-based MT targeting agents has been reported [ 24 ]. These acyl-substituted derivatives, conceived as analogs of nocodazole, represent other examples of carbazole scaffolds able to interact with the colchicine site of tubulin.…”

Section: Discussionmentioning

confidence: 99%

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

Peronne

Denarier

Rai

et al. 2020

Cancers

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Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

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Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells

Cited by 23 publications

References 39 publications

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Two antagonistic microtubule targeting drugs act synergistically to kill cancer cells

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells

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