Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design

Ji, Dezhong; Zhang, Lingzhi; Zhu, Qihua; Bai, Ying; Wu, Y Y; Xu, Yungen

doi:10.1016/j.ejmech.2018.12.040

Cited by 12 publications

(6 citation statements)

References 19 publications

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“…30,31 Recently, Yen and Ji D reported that KRAS mutation in lung cancer cells increased the levels of phosphorylated MEK and ERK, and then promoted proliferation and suppressed apoptosis in lung cancer cells. 6,32,33 MEK/ERK signaling plays an important role in KRAS mutant lung cancer cells. And it was found that the phosphorylation of MEK/ERK could be repressed by Anlotinib in this study.…”

Section: Discussionmentioning

confidence: 99%

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

Liu

Tan

et al. 2020

CMAR

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Background: With a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear. Materials and Methods: Cell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting. Results: Anlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells. Conclusion: Anlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC.

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Section: Discussionmentioning

confidence: 99%

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

Liu

Tan

et al. 2020

CMAR

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“…According to the pharmacological evaluation results, compound 22a (Figure 2, 4) shows a considerable antitumor effect due to the significant inhibition of ERK1/2 phosphorylation in HCT116 human CRC cells, exerting excellent inhibition potency with IC 50 values of 0.7 and 1.5 nM for ERK2 and ERK1, respectively. 45 In addition to in silico methods for structure-based drug design, some biochemical methods have also been used to screen for ERK inhibitors based on their competition. Interestingly, the 10 screened compounds share a common core structure consisting of a tertiary amine hub with three functionalized arginine-like cyclic guanidino branches, which binds to the substrate-recognition-related and complexassembly related D-recruitment site (DRS) to inhibit ERK2 activity and the phosphorylation of downstream substrates by disrupting critical protein interactions.…”

Section: Cancer Therapymentioning

confidence: 99%

“…Additionally, overlap modeling of the isoindolin-1-one and pyrrole-2-carboxamide scaffolds reveals that the benzyl moieties occupy the same cave under the glycine-rich loop. According to the pharmacological evaluation results, compound 22a (Figure , 4 ) shows a considerable antitumor effect due to the significant inhibition of ERK1/2 phosphorylation in HCT116 human CRC cells, exerting excellent inhibition potency with IC 50 values of 0.7 and 1.5 nM for ERK2 and ERK1, respectively …”

Section: Small-molecule Inhibitors Of Erk1/2 In Cancer Therapymentioning

confidence: 99%

Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors

Chen

et al. 2022

J. Med. Chem.

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Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream of the RAS-RAF-MEK-ERK (MAPK) pathway and is associated with the abnormal activation and poor prognosis of cancer. To date, several small-molecule inhibitors of RAS, RAF, and MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening the therapeutic efficacy of these inhibitors. Recently, selective inhibition of ERK1/2 has been regarded as a potential cancer therapeutic strategy that can not only effectively block the MAPK pathway but also overcome drug resistance caused by upstream mutations in RAS, RAF, and MEK. Herein, we summarize the oncogenic roles, key signaling network, and the single- and dual-target inhibitors of ERK1/2 in preclinical and clinical trials. Together, these inspiring findings shed new light on the discovery of more small-molecule inhibitors of ERK1/2 as candidate drugs to improve cancer therapeutics.

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“…Despite this, the BVD-523 (45) molecule was employed as a scaffold for designing orally bioavailable ERK1/2 inhibitors (46-48). The results showed that the hydroxymethylated derivative (47) showed to be 5-fold more active (IC 50 0.7 nM) on ERK2 and twice on ERK1 than the nonhydroxymethyl analog (48) (IC 50 35.6 nM) (Figure 3B); however, none of them was superior to BVD-523 (45) (IC 50 0.7 nM), indicating that the hydroxymethyl group is essential to biological activity (Ji et al, 2019). This can be attributed to better interaction with the target through H bonding.…”

Section: Analog Design Effects Of Hydroxymethylation On Drug/ Bioacti...mentioning

confidence: 99%

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties

et al. 2022

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Hydroxymethylation is a simple chemical reaction, in which the introduction of the hydroxymethyl group can lead to physical–chemical property changes and offer several therapeutic advantages, contributing to the improved biological activity of drugs. There are many examples in the literature of the pharmaceutical, pharmacokinetic, and pharmacodynamic benefits, which the hydroxymethyl group can confer to drugs, prodrugs, drug metabolites, and other therapeutic compounds. It is worth noting that this group can enhance the drug’s interaction with the active site, and it can be employed as an intermediary in synthesizing other therapeutic agents. In addition, the hydroxymethyl derivative can result in more active compounds than the parent drug as well as increase the water solubility of poorly soluble drugs. Taking this into consideration, this review aims to discuss different applications of hydroxymethyl derived from biological agents and its influence on the pharmacological effects of drugs, prodrugs, active metabolites, and compounds of natural origin. Finally, we report a successful compound synthesized by our research group and used for the treatment of neglected diseases, which is created from the hydroxymethylation of its parent drug.

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Discovery of potent, orally bioavailable ERK1/2 inhibitors with isoindolin-1-one structure by structure-based drug design

Cited by 12 publications

References 19 publications

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors

Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance Pharmacodynamic and Pharmacokinetic Properties

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