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Biocompatible Boron-Containing Prodrugs of Belinostat for the Potential Treatment of Solid Tumors.

ABSTRACT: Despite promising therapeutic utilities for treatment of hematological malignancies, histone deacetylase inhibitor (HDACi) drugs have not proven as effective in the treatment of solid tumors. To expand the clinical indications of HDACi drugs, we developed novel boron-containing prodrugs of belinostat (2), one of which efficiently releases active 2 through a cascade of reactions in cell culture and demonstrates activities comparable to 2 against a panel of cancer cell lines. Importantly, prodrug 7 is more efficacious than belinostat in vivo, not only inhibiting the growth of tumor but also reducing tumor volumes in an MCF-7 xenograft tumor model owing to its superior biocompatibility, which suggests its clinical potential in the treatment of solid tumors.

SUBMITTER: Zheng S

PROVIDER: S-EPMC5807862 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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Biocompatible Boron-Containing Prodrugs of Belinostat for the Potential Treatment of Solid Tumors.

Zheng Shilong S Guo Shanchun S Zhong Qiu Q Zhang Changde C Liu Jiawang J Yang Lin L Zhang Qiang Q Wang Guangdi G

ACS medicinal chemistry letters 20180108 2

Despite promising therapeutic utilities for treatment of hematological malignancies, histone deacetylase inhibitor (HDACi) drugs have not proven as effective in the treatment of solid tumors. To expand the clinical indications of HDACi drugs, we developed novel boron-containing prodrugs of belinostat (2), one of which efficiently releases active 2 through a cascade of reactions in cell culture and demonstrates activities comparable to 2 against a panel of cancer cell lines. ...[more]

PMID: 29456804

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Project description:Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.

Dataset Information

Biocompatible Boron-Containing Prodrugs of Belinostat for the Potential Treatment of Solid Tumors.

Publications

Biocompatible Boron-Containing Prodrugs of Belinostat for the Potential Treatment of Solid Tumors.

Similar Datasets

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