Structure based designing of thiazolidinone-pyrimidine derivatives as ERK2 inhibitors: Synthesis and in vitro evaluation

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.

KEYWORDS:

• Thiazolidinone-pyrimidine
• molecular dynamic simulations
• ERK2
• enzymatic assay

Acknowledgements

The authors would like to thank TCSMT (University of Turku), Finland for the research support. The authors also extend regards to ISF College of Pharmacy, Moga and Maharishi Markandeshwar (Deemed to University), Mullana, and CSIR-North East Institute of Science and Technology, Jorhat, India for their guidance and advice at all times.

Disclosure statement

No potential conflict of interest was reported by the author(s).