Recent advances in development of hetero-bivalent kinase inhibitors

Lee, Seungbeom; Kim, Jisu; Jo, Jeyun; Chang, Jae Won; Sim, Jaehoon; Yun, Hwayoung

doi:10.1016/j.ejmech.2021.113318

Cited by 17 publications

(19 citation statements)

References 184 publications

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“…Finally, compound 3 was reacted with bis-chloroacetyl piperazine to afford compound 8 in 85% isolated yield. The 1 H NMR and 13 C NMR spectroscopic data were in accordance with the assigned structures.…”

Section: Results and Discussion 21 Chemistrysupporting

confidence: 76%

“…based on phenolic unit. In continuation to our previous work, we aimed to exploit the hydrazine group in HTHQ (3) to synthesize new bivalent compounds to be employed as potential therapeutic agents [11][12][13]. As a result of resistance to current drugs and emerging new diseases there is constant need of obtaining antimicrobial and anticancer agents with minimal side effects.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Novel Bivalent Hydrazino-Thymohydroquinone Analogs Derived from Thymoquinone as Potential Antimicrobial Agents

et al. 2021

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In our previous work, it was reported that thymoquinone (TQ) and some thymohydroquinone (THQ) derivatives were used as precursors for the synthesis of potential anticancer agents. Hence, as a part of our ongoing program in the design of biologically active compounds derived from TQ scaffold we herein investigated the synthesis of homo-and heteronuclear thymol dimers tethered through various linkers such as ethylene, butylene, acetyl and N,N'-acetyl piperazine groups. The newly prepared compounds were examined as antimicrobial agents. Compounds 7 and 8 bearing a piperazine moiety exhibited highest antibacterial activity comparing to TQ, THQ and ampicillin especially against Staphylococcus aureus bacteria with MIC value of 16 µg/mL. All compounds showed moderate antifungal activity against Candida albicans and Aspergillus fumigatus. Together, the new TQ-based bivalent lead might be serving as a promising scaffold for development of novel and potent antimicrobial agents.

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Section: Results and Discussion 21 Chemistrysupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Bivalent Hydrazino-Thymohydroquinone Analogs Derived from Thymoquinone as Potential Antimicrobial Agents

et al. 2021

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“…In recent years, the bisubstrate approach has gained popularity for the construction of potent and selective inhibitors of PKs [ 10 , 11 , 12 ]. Bisubstrate inhibitors consist of two conjugated fragments, each targeting the binding site of a particular substrate.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family

et al. 2021

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We performed an X-ray crystallographic study of complexes of protein kinase PIM-1 with three inhibitors comprising an adenosine mimetic moiety, a linker, and a peptide-mimetic (d-Arg)6 fragment. Guided by the structural models, simplified chemical structures with a reduced number of polar groups and chiral centers were designed. The developed inhibitors retained low-nanomolar potency and possessed remarkable selectivity toward the PIM kinases. The new inhibitors were derivatized with biotin or fluorescent dye Cy5 and then applied for the detection of PIM kinases in biochemical solutions and in complex biological samples. The sandwich assay utilizing a PIM-2-selective detection antibody featured a low limit of quantification (44 pg of active recombinant PIM-2). Fluorescent probes were efficiently taken up by U2OS cells and showed a high extent of co-localization with PIM-1 fused with a fluorescent protein. Overall, the developed inhibitors and derivatives represent versatile chemical tools for studying PIM function in cellular systems in normal and disease physiology.

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“…This unique rational design permits the simultaneous binding to both ATP and peptide binding sites and thus making these compounds possess high selectivity and activity, which can meet the needs of the development of more potent and selective kinase inhibitors. 201 In addition, with the development of technology several new promising protein–protein interaction compounds (PPIs) have entered clinical studies. PPIs modulators can be a new strategy to design small molecules and peptide inhibitors targeting specific kinases domains.…”

Section: Challenges and Future Perspectivesmentioning

confidence: 99%

An overview of kinase downregulators and recent advances in discovery approaches

Wang

et al. 2021

Sig Transduct Target Ther

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Since the clinical approval of imatinib, the discovery of protein kinase downregulators entered a prosperous age. However, challenges still exist in the discovery of kinase downregulator drugs, such as the high failure rate during development, side effects, and drug-resistance problems. With the progress made through multidisciplinary efforts, an increasing number of new approaches have been applied to solve the above problems during the discovery process of kinase downregulators. In terms of in vitro and in vivo drug evaluation, progress was also made in cellular and animal model platforms for better and more clinically relevant drug assessment. Here, we review the advances in drug design strategies, drug property evaluation technologies, and efficacy evaluation models and technologies. Finally, we discuss the challenges and perspectives in the development of kinase downregulator drugs.

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Recent advances in development of hetero-bivalent kinase inhibitors

Cited by 17 publications

References 184 publications

Synthesis of Novel Bivalent Hydrazino-Thymohydroquinone Analogs Derived from Thymoquinone as Potential Antimicrobial Agents

Synthesis of Novel Bivalent Hydrazino-Thymohydroquinone Analogs Derived from Thymoquinone as Potential Antimicrobial Agents

Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family

An overview of kinase downregulators and recent advances in discovery approaches

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