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

Abstract

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.

Identification of differential polypharmacology between the PARP inhibitor rucaparib and its major metabolite

“…PLK2 has not been well explored in medicinal chemistry projects, as evidenced by the limited bioactivity data in ChEMBL database (version 30) (Gaulton et al, 2017). The vast majority of reported PLK2 inhibitors are derived from PLK1 projects and are the derivatives of pan-PLK inhibitor BI 2536 (Zhang et al, 2022b), largely limiting the specific study of PLK2. There is no selective, high-quality PLK2 chemical probe recommended by the Chemical Probes Portal (https://www.chemicalprobes.org/) (Antolin et al, 2022) and computational resources only identify a few selective inhibitors with modest potency (Antolin et al, 2018; Antolin et al, 2021b; Zhan et al, 2018).…”

Strategies of Targeting CK2 in Drug Discovery: Challenges, Opportunities, and Emerging Prospects

“…In the PI3K (phosphatidylinositol 3 kinase)/Akt pathway, CK2 phosphorylates Akt1 at Ser129 in the linker region and increases the level of mTOR (mammalian target of rapamycin) through inhibiting TSC1/2 (tuberous sclerosis complex 1/2) to promote cell growth and protein synthesis. , PTEN (phosphate and tension homology deleted on chromosome 10) catalyzes the conversion of PIP3 (phosphatidylinositol 3,4,5-triphosphate) to PIP2 (phosphatidylinositol 4,5-bisphosphate), which counteracts the PI3K/Akt signaling pathway, , and CK2 phosphorylates PTEN to mediate its inactivation and promote cell survival and metabolism (Figure ). , …”

Recent Advances in Synthetic Routes to Azacycles

“…Dialdehydrides have been used for the reaction of amines to produce azacyclic compounds. A series of reactions of dialdehydrides with amines to produce azacycles was reported before 2000 [ 31 , 32 , 33 , 34 ]. Most of these processes were achieved via reductive amination of aldehydes.…”

“…N -heterocycles have been employed in many industries, including as dyes, agrochemicals, and materials [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In pharmaceuticals, small-molecule drugs contain nitrogen-containing heterocycles and exhibit diverse bioactivities including anti-Alzheimer’s, antivirus, and anticancer behavior [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Thus, a series of studies on the synthesis and functionalization of many N -heterocyclic compounds, such as indoles, imidazoles, pyrrolidines, indolizines, and quinolines, as well as their application, has been carried out.…”