Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold

Lv, Xiao; Yang, Xiaoxiao; Zhan, Mei-Miao; Cao, Peichang; Zheng, Shihong; Peng, Ruihao; Han, Jihong; Xie, Zhouling; Tu, Zhengchao; Liao, Chenzhong

doi:10.1016/j.ejmech.2019.111769

Cited by 16 publications

(8 citation statements)

References 23 publications

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“…Compound 9 inhibited the phosphorylation level of the ALK F1174L mutant, facilitating a reduction in neuroblastoma cell proliferation. Another drug, compound 10 was synthesized to modulate the selectivity of BI 2536 for PLKs . The introduction of OCH 2 CH 2 OH improved the selectivity of compound 10 for PLK1 compared to that of BI 2536.…”

Section: Recent Progress In Plk1i Development For Cancer Therapymentioning

confidence: 99%

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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Section: Recent Progress In Plk1i Development For Cancer Therapymentioning

confidence: 99%

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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“…259 Several PLK1 inhibitors, including BI 2536, onvansertib, and BI 6727 (volasertib), have entered into clinical trials for cancer treatment and have shown promising anticancer effects. 260 However, whether PLK1 is an oncogene is under debate because data have shown that PLK1 can sometimes act as a tumor suppressor. 261 Both PLK2 and PLK3 are acidophilic kinases; however, our present knowledge of their biological roles is limited and fragmentary.…”

Section: Potential Kinase Inhibitors Formentioning

confidence: 99%

“…For type I (ATPcompetitive) or type II SMKIs, taking advantage of subtle differences among the binding sites in a kinase family might be a feasible strategy to design and identify selective kinase inhibitors. 260 To circumvent this, allosteric inhibitors (type III and type IV) targeting sites different from the orthostatic ATP-binding pockets have been discovered. Compared with ATPcompetitive inhibitors, due to the structural differences in their allosteric sites, allosteric inhibitors may have higher selectivity among the kinome, improved physiochemical properties, and better side effects or toxicity profiles.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

“…Among these five members, PLK1, having pivotal roles in mitosis, has significant clinical relevance and has been considered a bona fide target for the development of anticancer drugs . Several PLK1 inhibitors, including BI 2536, onvansertib, and BI 6727 (volasertib), have entered into clinical trials for cancer treatment and have shown promising anticancer effects . However, whether PLK1 is an oncogene is under debate because data have shown that PLK1 can sometimes act as a tumor suppressor …”

Section: Potential Kinase Inhibitors For Nononcologic Diseasesmentioning

confidence: 99%

“…The structural and sequence similarities of ATP-binding pockets make selective inhibition of different kinases a formidable task. For type I (ATP-competitive) or type II SMKIs, taking advantage of subtle differences among the binding sites in a kinase family might be a feasible strategy to design and identify selective kinase inhibitors …”

Section: Perspectives and Conclusionmentioning

confidence: 99%

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Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases

et al. 2021

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Great successes have been achieved in developing small-molecule kinase inhibitors as anticancer therapeutic agents. However, kinase deregulation plays essential roles not only in cancer but also in almost all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system disorders, viral infections, and malaria. Indeed, the first small-molecule kinase inhibitor for treatment of a nononcologic disease was approved in 2011 by the U.S. FDA. To date, 10 such inhibitors have been approved, and more are in clinical trials for applications other than cancer. This Perspective discusses a number of kinases and their small-molecule inhibitors for the treatment of diseases in nononcologic therapeutic fields. The opportunities and challenges in developing such inhibitors are also highlighted.

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Current progress in the targeted therapy of breast cancer: Structure–activity correlation and docking studies (2015–2021)

Pandey

Mondal

Kajal

et al. 2023

Archiv der Pharmazie

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Despite cancer research and therapy, breast cancer remains a complicated health crisis in women and represents a top biomedical research priority. Nowadays, breast cancer is an extremely heterogeneous disease and is known as the leading cause of death among women worldwide. The incidence and mortality rates of breast cancer have been increasing gradually for the past decades. Nowadays, common treatments for breast cancer are chemotherapy, endocrine therapy, immunotherapy, radiotherapy, and surgery. The most common targets in breast cancer treatment are human epidermal growth factor receptor 2 (HER2) and estrogen receptors.The literature suggests that several targets/pathways are also involved in the development of breast cancer, that is, poly(ADP-ribose) polymerase (PARP), bromodomain-containing protein 4 (BRD4), cyclin-dependent kinase 4/6 (CDK4/ 6), epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), polo-like kinase 1 (PLK1), phosphoinositide 3-kinases/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), histone deacetylase (HDAC), nuclear factor kappa B (NF-κB), PD-L1, and aromatase inhibitors.Meanwhile, the study of breast cancer is a hot topic in the current scenario of basic/clinical research. This review article provides information on different targets associated with breast cancer and summarizes the progress of current research on synthesized inhibitors as anti-breast cancer agents from 2015 to 2021. The review aims to provide structure-activity relationship and docking studies for designing novel compounds for breast cancer therapy.

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Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold

Cited by 16 publications

References 23 publications

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

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

Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases

Current progress in the targeted therapy of breast cancer: Structure–activity correlation and docking studies (2015–2021)

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