Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles

Hymel, David; Tsuji, Kohei; Grant, Robert A.; Chingle, Ramesh; Kunciw, D.L.; Yaffe, Michael B.; Burke, Terrence R.

doi:10.1039/d1ob01120k

Cited by 6 publications

(7 citation statements)

References 65 publications

(102 reference statements)

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“…Novel approaches to develop high-affinity agents targeting PLK1 have explored agents targeting both the binding pocket and cryptic pockets (only revealed after ligand binding). Hymel and colleagues had leveraged this approach to develop several novel macrocyclic peptide mimetics with high affinity for the PLK1 PBD [186]. Characterization of these agents revealed nanomolar IC 50 values and 140-and 300-fold specificity over the PBDs of PLK2 and PLK3, respectively [186].…”

Section: Plk1 Inhibitionmentioning

confidence: 99%

The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors

Moore

Gheghiani

2023

Cells

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Polo-like kinase 1 (PLK1) is a serine/threonine kinase with more than 600 phosphorylation substrates through which it regulates many biological processes, including mitosis, apoptosis, metabolism, RNA processing, vesicle transport, and G2 DNA-damage checkpoint recovery, among others. Among the many PLK1 targets are members of the FOX family of transcription factors (FOX TFs), including FOXM1, FOXO1, FOXO3, and FOXK1. FOXM1 and FOXK1 have critical oncogenic roles in cancer through their antagonism of apoptotic signals and their promotion of cell proliferation, metastasis, angiogenesis, and therapeutic resistance. In contrast, FOXO1 and FOXO3 have been identified to have broad functions in maintaining cellular homeostasis. In this review, we discuss PLK1-mediated regulation of FOX TFs, highlighting the effects of PLK1 on the activity and stability of these proteins. In addition, we review the prognostic and clinical significance of these proteins in human cancers and, more importantly, the different approaches that have been used to disrupt PLK1 and FOX TF-mediated signaling networks. Furthermore, we discuss the therapeutic potential of targeting PLK1-regulated FOX TFs in human cancers.

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Section: Plk1 Inhibitionmentioning

confidence: 99%

The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors

Moore

Gheghiani

2023

Cells

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“…In recent years, researchers have developed many novel small-molecule PLK1i, including KD inhibitors and PBD inhibitors. Simultaneously, the application of new technologies has promoted the discovery of new inhibitors such as PLK1 selective inhibitors, dual-target inhibitors (e.g., PLK1-BRD4 and PLK1-NEK2 dual inhibitors), , PLK1 allosteric inhibitors, proteolysis targeting chimeras (PROTACs), , hydrophobic tags, , and protein–protein interaction (PPI) inhibitors. These inhibitors bind to the KD or PBD of PLK1 with high potency, high selectivity, and favorable PK.…”

Section: Recent Progress In Plk1i Development For Cancer Therapymentioning

confidence: 99%

“…On the basis of PLK1 PBD phosphate-dependent PPIs, the pentapeptide phosphate PBD-binding ligand PLHSpT, and a proximal cryptic pocket of an important signaling module, researchers designed a macrocyclic peptide mimetic, compound 50 . The large loop of 50 reduced the conformational flexibility and enhanced the ligand affinity . A new unnatural amino acid was used as the closed loop connection point and simultaneously induced the correct orientation of the above-mentioned cryptic pocket and pT residues.…”

Section: Recent Progress In Plk1i Development For Cancer Therapymentioning

confidence: 99%

“…The large loop of 50 reduced the conformational flexibility and enhanced the ligand affinity. 121 A new unnatural amino acid was used as the closed loop connection point and simultaneously induced the correct orientation of the above-mentioned cryptic pocket and pT residues. In conclusion, PLHSpT derivatives have provided rich information useful for understanding the binding surface of the PLK1 PBD, which is facilitating the identification of selective PLK1 PBD inhibitors.…”

Section: Plk1imentioning

confidence: 99%

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Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential

Zhang

Wang

et al. 2022

J. Med. Chem.

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Polo-like kinase 1 (PLK1) plays an important role in a variety of cellular functions, including the regulation of mitosis, DNA replication, autophagy, and the epithelial–mesenchymal transition (EMT). PLK1 overexpression is often associated with cell proliferation and poor prognosis in cancer patients, making it a promising antitumor target. To date, at least 10 PLK1 inhibitors (PLK1i) have been entered into clinical trials, among which the typical kinase domain (KD) inhibitor BI 6727 (volasertib) was granted “breakthrough therapy designation” by the FDA in 2013. Unfortunately, many other KD inhibitors showed poor specificity, resulting in dose-limiting toxicity, which has greatly impeded their development. Researchers recently discovered many PLK1i with higher selectivity, stronger potency, and better absorption, distribution, metabolism, and elimination (ADME) characteristics. In this review, we emphasize the structure–activity relationships (SARs) of PLK1i, providing insights into new drugs targeting PLK1 for antitumor clinical practice.

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“…Protein–protein interactions (PPIs) tune biological processes and are deeply involved in the development and progression of diseases ( Milroy et al, 2014 ). Proteomic investigations pointed out that hundreds of thousands of PPIs occur ( Stumpf et al, 2008 ); hence, considerable pharmaceutical efforts are focused on their modulation for therapeutic intervention ( Barnard et al, 2015 ; Scott et al, 2016 ; Feng et al, 2017 ; Stefan et al, 2018 ; Hymel et al, 2021 ). In this context, small-molecule approaches often fail mainly because such a compound for its size cannot establish a suitable number of favorable interactions, thus hampering this traditional pharmaceutical approach.…”

Section: Proteomimetics Of Natural Inhibitors Of Jak-statmentioning

confidence: 99%

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Manna

Benedictis

Marasco

2022

Front. Mol. Biosci.

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The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein–protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK–STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

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Design and synthesis of a new orthogonally protected glutamic acid analog and its use in the preparation of high affinity polo-like kinase 1 polo-box domain – binding peptide macrocycles

Abstract: Targeting protein – protein interactions (PPIs) has emerged as important area of discovery for anticancer therapeutic development. In the case of phospho-dependent PPIs, such as the polo-like kinase 1 (Plk1)...

Cited by 6 publications

References 65 publications

The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors

The Role of Polo-Like Kinase 1 in Regulating the Forkhead Box Family Transcription Factors

Polo-like Kinase 1 Inhibitors in Human Cancer Therapy: Development and Therapeutic Potential

Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

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