Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

Patel, Harish M.; Chuckowree, Irina; Coxhead, Peter; Guille, Matthew; Wang, Minghua; Zuckermann, Alexandra M.E.; Williams, Robin S. B.; Librizzi, Mariangela; Paranal, Ronald M.; Bradner, James E.; Spencer, John

doi:10.1039/c4md00211c

Cited by 22 publications

(32 citation statements)

References 38 publications

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“…In the latter approach, using a labile linker such as an ester can result in the release of the two drugs when cleaved by plasma esterases [99]. The rationale behind the development of hybrid drugs is the simultaneous presence of chemical entities in the cell, which may act in a synergistic manner to augment potency and reduce side effects [101,102,114]. This is in contrast to the administration of individual drugs that will inevitably be delivered to the target site at different rates and efficacies.…”

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 97%

“…However, synergistic effects have been observed when HDAC inhibitors have been used in combination with other drugs, including a significant decrease in cell viability when used in conjunction with Sorafenib, a dual action VEGFR/PDGFR and RAF kinase inhibitor [119,120]. This has prompted the development of HDAC inhibitor containing hybrid agents, for example, a recently synthesized dual HDAC/VEGFR2 inhibitor [114]. Another promising agent, CUDC-101, developed by Curis, was found to simultaneously inhibit HDAC class I/II, EGFR and HER2 and exhibited antiproliferative effects in vitro and growth inhibition in various cancer xenograft models [121].…”

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 99%

“…This is in contrast to the administration of individual drugs that will inevitably be delivered to the target site at different rates and efficacies. Hybrid compounds can often display improved bioavailability and present more predictable pharmacokinetic and pharmacodynamic profiles in comparison to individual agents [102,114].…”

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 99%

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Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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Targeting the translational machinery has emerged as a promising therapeutic option for cancer treatment. Cancer cells require elevated protein synthesis and exhibit augmented activity to meet the increased metabolic demand. Eukaryotic translation initiation factor 4E is necessary for mRNA translation, its availability and phosphorylation are regulated by the PI3K/AKT/mTOR and MNK1/2 pathways. The phosphorylated form of eIF4E drives the expression of oncogenic proteins including those involved in metastasis. In this article, we will review the role of eIF4E in cancer, its regulation and discuss the benefit of dual inhibition of upstream pathways. The discernible interplay between the MNK and mTOR signaling pathways provides a novel therapeutic opportunity to target aggressive migratory cancers through the development of hybrid molecules.

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Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 97%

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 99%

Section: Therapeutic Targeting and The Concept Of Hybrid Inhibitorsmentioning

confidence: 99%

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Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

2017

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“…HDAC inhibitor-based compounds were designed to incorporate the VEGFR2 inhibitor Semaxanib (SU5416) [35]. The study provided preliminary data concerning antiproliferative activity, biochemical inhibition and SAR of the hybrids.…”

Section: Hybrids Incorporating Hdac Inhibitors and Target-specific Agmentioning

confidence: 99%

Perspectives in the development of hybrid bifunctional antitumour agents

Musso

Dallavalle

Zunino

2015

Biochemical Pharmacology

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In spite of the development of a large number of novel target-specific antitumour agents, the single-agent therapy is in general not able to provide an effective durable control of the malignant process. The limited efficacy of the available agents (both conventional cytotoxic and novel target-specific) reflects not only the expression of defence mechanisms, but also the complexity of tumour cell alterations and the redundancy of survival pathways, thus resulting in tumour cell ability to survive under stress conditions. A well-established strategy to improve the efficacy of antitumour therapy is the rational design of drug combinations aimed at achieving synergistic effects and overcoming drug resistance. An alternative strategy could be the use of agents designed to inhibit simultaneously multiple cellular targets relevant to tumour growth/survival. Among these novel agents are hybrid bifunctional drugs, i.e. compounds resulting by conjugation of different drugs or containing the pharmocophores of different drugs. This strategy has been pursued using various conventional or target-specific agents (with DNA damaging agents and histone deacetylase inhibitors as the most exploited compounds). A critical overview of the most representative compounds is provided with emphasis on the HDAC inhibitor-based hybrid agents. In spite of some promising results, the actual pharmacological advantages of the hybrid agents remain to be defined. This commentary summarizes the recent advances in this field and highlights the pharmacological basis for a rational design of hybrid bifunctional agents.

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“…Recently, multi-acting inhibitors against HDAC and RTK have been reported as potent anticancer agent [41][42][43][44] . In this paper, a series of hybrids with 4-anilinoquinazoline and hydroxamic acid motifs were discovered as novel VEGFR-2/HDAC dual inhibitors.…”

mentioning

confidence: 99%

Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

Peng

Ren

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

Cited by 22 publications

References 38 publications

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

Perspectives in the development of hybrid bifunctional antitumour agents

Hybrids from 4-anilinoquinazoline and hydroxamic acid as dual inhibitors of vascular endothelial growth factor receptor-2 and histone deacetylase

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