Scaffold-based analysis of nonpeptide oncogenic FTase inhibitors using multiple similarity matching, binding affinity scoring and enzyme inhibition assay

Wang, Qifei; Chen, Fei; Liu, Peng; Mu, Yushu; Sun, Shibin; Yuan, Xulong; Shang, Pan; Ji, Bo

doi:10.1016/j.jmgm.2021.107898

Cited by 4 publications

(2 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FTase, one of the tansferase enzymes, targets Ras proteins, adding a farnesyl group to it. After the essential transfer step, the activity of the Ras protein has been inhibited by Ftase [86,87]. Therefore, FTase enzyme and the downstream pathways of the Ras protein are considered to be one of the most important groups of targets that can be medicated in cancer therapy [88].…”

Section: Ras Kinase Inhibitorsmentioning

confidence: 99%

The Role of Kinase Inhibitors in Cancer Therapies

Kursunluoglu¹,

Erdogan²,

Cagatay³

et al. 2021

Protein Kinases - Promising Targets for Anticancer Drug Research

View full text Add to dashboard Cite

Protein kinases are enzymes that transfer a phosphate group to the threonine, serine, or tyrosine residues of the target protein, regulating its activity. The activity of these enzymes are very important and strictly regulated in the cell as they promote cell proliferation, survival, and migration. In the case of any dysregulation of these enzymes, they can be associated with cancer initiation and progression. Small-molecule kinase inhibitors approved by the FDA for their improved clinical benefits are currently used in targeted therapy for the treatment of various cancers. So far, there are 62 FDA-approved therapeutic agents targeting different protein kinases, eight of which were approved in 2020. Today, kinase inhibitors are used as FDA approved cancer agents and newly developed ones are evaluated in clinical trials. Those protein kinase inhibitors can be grouped as growth factor receptor inhibitors, Ras/Raf/Mek inhibitors, phosphoinositide 3-kinase (PI3K) and cyclin dependent kinase inhibitors, other targets, and agents such as protein kinase c and 3 phosphoinositide-dependent kinase 1. In this chapter, these kinases, their pathways, and their inhibitors will be discussed in detail.

show abstract

Section: Ras Kinase Inhibitorsmentioning

confidence: 99%

The Role of Kinase Inhibitors in Cancer Therapies

Kursunluoglu¹,

Erdogan²,

Cagatay³

et al. 2021

Protein Kinases - Promising Targets for Anticancer Drug Research

View full text Add to dashboard Cite

show abstract

“…Recently, we have successfully employed multiple similarity matching, binding affinity scoring, and enzyme inhibition assay to perform scaffold-based analysis of the affinity, selectivity, and cross-reactivity of various nonpeptide inhibitors across ontology-enriched, diseaseassociated enzyme mutants. 20 Considering that the upstream YAP WW1/2 domains and, particularly, their binding partners and recognition specificity still remain largely unclear, we herein integrated in silico structural bioinformatics modeling and in vitro fluorescence spectroscopy assay to investigate the molecular mechanism and biological implication underlying the complicated PMIs of YAP with partners, attempting to systematically (1) analyze the potential partner proteins of YAP WW1/2 domains, (2) to identify the recognition sites of YAP WW1/2 domains in their interacting partners, (3) to define the sequence requirement for the recognition sites, (4) to compare the PRM preferences between the recognition sites of YAP WW1 and WW2 domains, (5) to profile the recognition site selectivity between the YAP WW1 and WW2 domains, and (6) to ascertain the molecular origin of the selectivity.…”

Section: Introductionmentioning

confidence: 99%

Systematic profiling and identification of the peptide‐mediated interactions between human Yes‐associated protein and its partners in esophageal cancer

Chen

Wang

et al. 2021

J of Molecular Recognition

Self Cite

View full text Add to dashboard Cite

Human Yes-associated protein (YAP) is involved in the Hippo signaling pathway and serves as a coactivator to modulate gene expression, which contains a transactivation domain (TD) responsible for binding to the downstream TEA domain family (TEAD) of transcription factors and two WW1/2 domains that recognize the proline-rich motifs (PRMs) present in a variety of upstream protein partners through peptidemediated interactions (PMIs). The downstream YAP TD-TEAD interactions are closely associated with gastric cancer, and a number of therapeutic agents have been developed to target the interactions. In contrast, the upstream YAP WW1/2-partner interactions are thought to be involved in esophageal cancer but still remain largely unexplored. Here, we attempted to elucidate the complicated PMIs between the YAP WW1/2 domains and various PRMs of YAP-interacting proteins. A total of 106 peptide segments carrying the class I WW-binding motif [P/L]Px[Y/P] were

show abstract

Peptide scaffold‐derived peptidomimetic farnesyltransferase inhibitors

Yang

Wang

et al. 2021

J Chinese Chemical Soc

View full text Add to dashboard Cite

Human protein farnesyltransferase (FTase) is involved in many essential signal transduction proteins and has been explored as druggable targets of diverse diseases such as cancer and inflammation. Here, we propose a new strategy termed as Peptide Scaffold‐derived Peptidomimetic FTase Inhibitors (PSPFI) to discover peptidomimetic lead molecular entities that can inhibit FTase. The strategy first defines a PSPFI‐oriented peptidomimetic library that contains >30,000 sulfhydryl/thioether‐carrying peptidomimetics, and then employs molecular docking calculation, multiple similarity analysis, structural minimization, and affinity scoring to screen against the library, in order to discover those peptidomimetics that share high similarity with the core binding module (CBM) of FTase Rap2a peptide substrate in 2D‐chemistry, 3D‐conformation, pharmacophore, and nonbonded pattern, as well as exhibit high theoretical affinity to FTase. Totally 56 hit peptidomimetics were identified from the library, from which we manually select 6 structurally diverse, purchasable peptidomimetics to perform FTase assays. Consequently, four are determined as potent FTase inhibitors (IC50 < 1 μM); their inhibitory activity is moderately lower than the sophisticated FTase inhibitor Tipifarnib and considerably higher than the native CBM peptide. These peptidomimetic ligands share similar extended conformation, binding mode, and Zn2+ coordination with Rap2a CBM peptide in FTase active site, but would have a different inhibition mechanism to Tipifarnib.

show abstract

Scaffold-based analysis of nonpeptide oncogenic FTase inhibitors using multiple similarity matching, binding affinity scoring and enzyme inhibition assay

Cited by 4 publications

References 40 publications

The Role of Kinase Inhibitors in Cancer Therapies

The Role of Kinase Inhibitors in Cancer Therapies

Systematic profiling and identification of the peptide‐mediated interactions between human Yes‐associated protein and its partners in esophageal cancer

Peptide scaffold‐derived peptidomimetic farnesyltransferase inhibitors

Contact Info

Product

Resources

About