Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors

Tiwari, Rakesh; Brown, Alex; Sadeghiani, N.; Shirazi, Amir Nasrolahi; Bolton, Jared; Tse, Amanda; Verkhivker, Gennady M.; Parang, Keykavous; Sun, Gongqin

doi:10.1002/cmdc.201600387

Cited by 14 publications

(15 citation statements)

References 53 publications

(104 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…(3) Dasatinib completely blocked Src phosphorylation on Y527 by another PTK, Csk [39], and significantly inhibited Src autophosphorylation on Y416. This is consistent with earlier reports that both Src and Csk are sensitive to dasatinib [40]. Dasatinib also appeared to partially inhibit Mek and Erk activation, suggestive of crosstalk between Src and the MAP kinase pathway.…”

Section: Src Ir/igf-1r/akt Signaling and The Map Kinase Pathway Are supporting

confidence: 92%

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Shen

Yang

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Quantifying the response of cancer cells to a drug, and understanding the mechanistic basis of the response, are the cornerstones for anti-cancer drug discovery. Classical single target-based IC50 measurements are inadequate at describing cancer cell responses to targeted drugs. In this study, based on an analysis of targeted inhibition of colorectal cancer cell lines, we develop a new biphasic mathematical model that accurately describes the cell–drug response. The model describes the drug response using three kinetic parameters: ratio of target-specific inhibition, F1, potency of target-specific inhibition, Kd1, and potency of off-target toxicity, Kd2. Determination of these kinetic parameters also provides a mechanistic basis for predicting effective combination targeted therapy for multi-driver cancer cells. The experiments confirmed that a combination of inhibitors, each blocking a driver pathway and having a distinct target-specific effect, resulted in a potent and synergistic blockade of cell viability, improving potency over mono-agent treatment by one to two orders of magnitude. We further demonstrate that mono-driver cancer cells represent a special scenario in which F1 becomes nearly 100%, and the drug response becomes monophasic. Application of this model to the responses of >400 cell lines to kinase inhibitor dasatinib revealed that the ratio of biphasic versus monophasic responses is about 4:1. This study develops a new mathematical model of quantifying cancer cell response to targeted therapy, and suggests a new framework for developing rational combination targeted therapy for colorectal and other multi-driver cancers.

show abstract

Section: Src Ir/igf-1r/akt Signaling and The Map Kinase Pathway Are supporting

confidence: 92%

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Shen

Yang

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dasatinib is a multitargeted inhibitor. Previous studies demonstrated that dasatinib exhibited strong inhibition of ABL and BCR/ABL tyrosine kinases and broad activity against Src-family tyrosine kinases (22–24). Dasatinib is a second-generation tyrosine kinase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis

Guo

Yang

et al. 2019

Front. Immunol.

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that primarily manifests as persistent synovitis and progressive joint destruction. Imatinib exhibited a therapeutic effect in murine collagen-induced arthritis (CIA) via selective inhibition tyrosine kinases. The second-generation tyrosine kinase inhibitor dasatinib exhibits more durable hematological and cytogenetic effects and more potency compared to imatinib. However, the effect of dasatinib on CIA is poorly understood. The present study investigated the treatment effect of dasatinib on autoimmune arthritis. We demonstrated that dasatinib alleviated arthritis symptoms and histopathological destruction in CIA mice. Dasatinib treatment inhibited the production of proinflammatory cytokines including IL-1β, TNF-α, and IL-6, and promoted the production of the anti-inflammatory cytokine IL-10. Dasatinib treatment also suppressed the expression of anti-mouse CII antibodies including total IgG, IgG1, IgG2, and IgG2b, in CIA mice. We further demonstrated that dasatinib inhibited the migration and proliferation of fibroblast-like synoviocytes (FLS) from RA patients and promoted FLS apoptosis. The mRNA expression of MMP13, VEGF, FGF, and DKK1 was down-regulated in FLS treated with dasatinib. Our findings suggest that dasatinib exhibited treatment effects on CIA mice and that FLS are an important target cell of dasatinib treatment in autoimmune arthritis.

show abstract

“…Wild‐type human Abl catalytic domain, full‐length Csk, FGFR1 catalytic domain, and full‐length Lck were cloned into pGEX‐4 T‐1 plasmid using BamHI and EcoRI restriction sites as described previously and expressed in E. coli DH5α. All constructs were verified by sequence analysis.…”

Section: Methodsmentioning

confidence: 99%

Structural versatility that serves the function of the HRD motif in the catalytic loop of protein tyrosine kinase, Src

Cui

Sun

2018

Protein Science

Self Cite

View full text Add to dashboard Cite

Site‐directed mutagenesis is a traditional approach for structure–function analysis of protein tyrosine kinases, and it requires the generation, expression, purification, and analysis of each mutant enzyme. In this study, we report a versatile high throughput bacterial screening system that can identify functional kinase mutants by immunological detection of tyrosine phosphorylation. Two key features of this screening system are noteworthy. First, instead of blotting bacterial colonies directly from Agar plates to nitrocellulose membrane, the colonies were cultured in 96‐well plates, and then spotted in duplicate onto the membrane with appropriate controls. This made the screening much more reliable compared with direct colony blotting transfer. A second feature is the parallel use of a protein tyrosine phosphatase (PTP)‐expressing host and a non‐PTP‐expressing host. Because high activity Src mutants are toxic to the host, the PTP system allowed the identification of Src mutants with high activity, while the non‐PTP system identified Src mutants with low activity. This approach was applied to Src mutant libraries randomized in the highly conserved HRD motif in the catalytic loop, and revealed that structurally diverse residues can replace the His and Arg residues, while the Asp residue is irreplaceable for catalytic activity.

show abstract

Design, Synthesis, and Evaluation of Dasatinib–Amino Acid and Dasatinib–Fatty Acid Conjugates as Protein Tyrosine Kinase Inhibitors

Cited by 14 publications

References 53 publications

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Biphasic Mathematical Model of Cell–Drug Interaction That Separates Target-Specific and Off-Target Inhibition and Suggests Potent Targeted Drug Combinations for Multi-Driver Colorectal Cancer Cells

Treatment Effects of the Second-Generation Tyrosine Kinase Inhibitor Dasatinib on Autoimmune Arthritis

Structural versatility that serves the function of the HRD motif in the catalytic loop of protein tyrosine kinase, Src

Contact Info

Product

Resources

About