Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties

Wu, Jingde; Cui, Yingjie; Zhou, Yigang; Tang, Liang‐Fu; Zhang, Chengmei; Liu, Zhao-Peng

doi:10.1007/s10637-019-00753-z

Cited by 6 publications

(8 citation statements)

References 40 publications

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“…In previous investigations, the oral administration of LL01 as a 0.5% MC (carboxymethylcellulose sodium) suspension resulted in a 50% reduction in tumor volume in an established HepG2 xenograft model. 50 ID09 and ID33 exhibited slightly better orally antitumor efficiency than that of LL01 despite the formulation differences.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…49 As a hydroxamic acid, LL02 was found unstable in the liver microsome stability assay, while the acetamide LL01 was metabolically stable with acceptable pharmacokinetic (PK) properties. 50 Further studies confirmed that LL01 was not a P-gp substrate and effective for multidrug-resistant tumor cells. In HepG2 and KB/V tumor models, LL01 effectively inhibited tumor growth via oral or subcutaneous administration.…”

Section: ■ Introductionmentioning

confidence: 99%

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SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors

Cui

Liu

et al. 2020

J. Med. Chem.

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Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01–ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Log P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors

Cui

Liu

et al. 2020

J. Med. Chem.

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“…Second, our approach allows the replacement of an MTA or a self-assembled protein of interest, to be fully characterized for its effect on normal cell functions. Thus, all the colchicine-derivatives and CSIs, which have recently gained interest in treating multi-drug resistant cell lines (104)(105)(106)(107)(108), can be potentially tested for their efficacy and toxicity on MT dynamics and cell functions and compared to the narrow therapeutic window of colchicine.…”

Section: Discussionmentioning

confidence: 99%

Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine

Hemmat

Braman

Escalante

et al. 2020

Preprint

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Microtubule-directed anti-cancer drugs, such as paclitaxel, vinblastine, and colchicine, disrupt cell mitosis through suppression of microtubule dynamics ("kinetic stabilization"). However, while the molecular mechanisms of paclitaxel and vinblastine act as pseudoand true-kinetic stabilizers, respectively, the molecular mechanism of colchicine has remained enigmatic since it requires explanation of both the slow kinetics of the drug and suppression of microtubule dynamics. In this work, we applied an integrated multi-scale modeling-experimental approach to systematically characterize the microtubule targeting agent (MTA) colchicine. We found that colchicine stabilizes microtubule dynamics significantly both in vivo and in vitro in a time and concentration-dependent manner. Molecular modeling results suggest that tubulin's binding pocket is accessible to the drug for only 15% of the simulation trajectory time in straight and 82% in curved conformation on average, confirming that colchicine mainly binds to free tubulin. Molecular dynamics simulations show that there are conformational changes at longitudinal and lateral residues of GTP-tubulin-colchicine compared to a lattice tubulin structure, explaining why further incorporation of tubulin dimers to a tubulin-colchicine complex at a protofilament tip is unfavorable. Thermokinetic modeling of microtubule assembly shows that colchicine bound at fractions as low as ~0.008 to free tubulin can poison the ends of protofilaments with a Poisson distribution and thus, reduce the microtubule growth rate, while stabilizing the tubulin lateral bond and reducing the microtubule shortening rate, i.e. true kinetic stabilization. This study suggests new strategies for colchicine administration to improve the therapeutic window in the treatment of cancer and inflammatory diseases. Significance StatementColchicine is an ancient microtubule targeting agent (MTA) known to attenuate microtubule (MT) dynamics but its cancer treatment efficacy is often limited by lack of a detailed understanding of the drug's mechanism of action. The primary goal of this study was to perform a multi-scale systematic analysis of molecular mechanism of action of colchicine. The analysis indicates that unlike paclitaxel and vinblastine, colchicine poisons the ends of protofilaments of MTs at low fractions bound to tubulin, in a time-dependent manner. Our results suggest new insights into improvement of the clinical administration of colchicine and new colchicine-site inhibitors.

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“…However, their way to the application has not been smooth due to the difficulties in development. A previous study has reported LL01, an indenoprazole compound combined with colchicine-binding site (CBS), as a potent MDA [12]. Disappointingly, its low solubility and logP limit its clinical application [12,13].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

“…A previous study has reported LL01, an indenoprazole compound combined with colchicine-binding site (CBS), as a potent MDA [12]. Disappointingly, its low solubility and logP limit its clinical application [12,13]. Hence, ID09, a new optimized derivative of LL01 with excellent aqueous solubility and favorable logP value, was designed and synthesized [13].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

ID09, A Newly-Designed Tubulin Inhibitor, Regulating the Proliferation, Migration, EMT Process and Apoptosis of Oral Squamous Cell Carcinoma

Feng¹,

Yang²,

Wang³

et al. 2022

Int. J. Biol. Sci.

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Microtubules, a major target in oral squamous cell carcinoma (OSCC) chemotherapy, contribute to multiple malignant biological behaviors, including proliferation, migration, and epithelial-mesenchymal transition (EMT). Surpassing traditional tubulin inhibitors, ID09 emerges with brilliant solubility, photostability, and drug-sensitivity in multidrug-resistant cells. Its anti-tumor effects have been briefly verified in lung adenocarcinoma and hepatocellular carcinoma. However, whether OSCC is sensitive to ID09 and the potential mechanisms remain ambiguous, which are research purposes this study aimed to achieve. Various approaches were applied, including clone formation assay, flow cytometry, wound healing assay, Transwell assay, cell counting kit-8 assay, Western blot, qRT-PCR, and in vivo experiment. The experimental results revealed that ID09 not only contributed to cell cycle arrest, reduced migration, and reversed EMT, but accelerated mitochondria-initiated apoptosis. Remarkably, Western blot detected diminishment in expression of Mcl-1 due to the deactivation of Ras-Erk pathway, resulting in ID09-induced apoptosis, proliferation and migration suppression, which could be offset by Erk1/2 phosphorylation agonist Ro 67-7476. This study initially explored the essential role Mcl-1 played and the regulatory effect of Ras-Erk pathway in anti-cancer process triggered by tubulin inhibitor, broadening clinical horizon of tubulin inhibitors in oral squamous cell carcinoma chemotherapy application.

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Tubulin colchicine site binding agent LL01 displays potent antitumor efficiency both in vitro and in vivo with suitable drug-like properties

Cited by 6 publications

References 40 publications

SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors

SAR Investigation and Discovery of Water-Soluble 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazoles as Potent Tubulin Polymerization Inhibitors

Poisson poisoning as the mechanism of action of the microtubule-targeting agent colchicine

ID09, A Newly-Designed Tubulin Inhibitor, Regulating the Proliferation, Migration, EMT Process and Apoptosis of Oral Squamous Cell Carcinoma

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