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Published on: February 9, 2021
Structure based designing of thiazolidinone-pyrimidine derivatives as ERK2 inhibitors: Synthesis and in vitro
S Pathania1,2, P K Singh3, R K Narang1
1Department of Pharmaceutical Chemistry, ISF College of Pharmacy, Moga, India.
Abstract:
Breast cancer has been associated with an overexpression of various molecular targets; accordingly, various target-specific chemotherapeutic agents have been developed. Inhibition of ERK2, a member of MAPK pathway, is an important target involved in the treatment of both oestrogen receptor-positive and triple-negative breast cancer. Thus, in continuation of our previous work on the ERK2 target, we here report novel inhibitors of this kinase. Out of three lead molecules reported in our previous study, we selected the thiazolidinone-pyrimidine scaffold for further development of small molecule inhibitors of ERK2. Analogues of the lead molecule were docked in the target kinase, followed by molecular dynamic simulations and MM-GBSA calculations. Analogues maintaining key interactions with amino acid residues in the ATP-binding domain of ERK2 were selected and duly synthesized. In vitro biochemical evaluation of these molecules against ERK2 kinase disclosed that two molecules possess significant kinase inhibitory potential with IC50 values ≤ 0.5 µM.
Insights
Researchers developed novel small molecule inhibitors targeting ERK2, a key protein in breast cancer progression. Two synthesized compounds showed significant ERK2 kinase inhibitory potential, offering new therapeutic avenues for breast cancer treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Breast cancer often involves overexpression of molecular targets, necessitating targeted therapies.
- ERK2, a mitogen-activated protein kinase (MAPK) pathway member, is a crucial target for both estrogen receptor-positive and triple-negative breast cancer.
Purpose of the Study:
- To develop novel small molecule inhibitors targeting the ERK2 kinase.
- To build upon previous research by optimizing a thiazolidinone-pyrimidine scaffold for ERK2 inhibition.
Main Methods:
- In silico molecular docking of analogues into the ERK2 ATP-binding domain.
- Molecular dynamic simulations and MM-GBSA calculations to assess binding affinity.
- Synthesis of selected analogues and in vitro biochemical evaluation against ERK2.
Main Results:
- Identification of analogues that maintain critical interactions within the ERK2 ATP-binding site.
- Synthesis and successful in vitro evaluation of novel ERK2 inhibitors.
- Two compounds demonstrated significant kinase inhibitory potential with IC50 values less than or equal to 0.5 µM.
Conclusions:
- The study successfully identified and synthesized novel small molecules with potent ERK2 inhibitory activity.
- These findings provide promising lead compounds for the development of new breast cancer therapeutics targeting the MAPK pathway.
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