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Rational Design of a Potent Pan-Pim Kinases Inhibitor with a Rhodanine-Benzoimidazole Structure
Yuichi Sawaguchi1, Ryuta Yamazaki2, Yukiko Nishiyama2
1Yakult Central Institute, Yakult Honsha Co., Ltd., Tokyo, Japan yuichi-sawaguchi@yakult.co.jp.
Background/Aim:
The serine/threonine Pim kinases are overexpressed in various types of solid carcinomas and hematological malignancies, and contribute to regulating cell-cycle progression and cell survival. The aim of this study was to discover a novel pan-Pim kinases inhibitor with potent anti-proliferative activities against cancer cell lines.
Materials And Methods:
We screened a panel of small molecule compounds for their ability to inhibit Pim-1 kinase activity, and the hit compound was optimized using the docking analysis to Pim-1. We evaluated kinase-inhibition activities of the rationally-designed compound against Pim-1, 2, 3 and another five kinases. Furthermore, in order to characterize the cellular activities, both solid and hematological cancer cell lines treated with the compound were subjected to anti-proliferative assay, western blotting, FACS and apoptosis assays.
Results:
We discovered a pan-Pim kinases inhibitor, compound 1, with a rhodanine-benzylidene structure via Pim-1 inhibitor screening. Using docking analysis of compound 1 and Pim-1, we optimized it and found a potent- and selective-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Compound 2 inhibited Pim-1, 2, 3 with IC50 values of 16, 13, and 6.4 nM, respectively, and suppressed proliferation of solid and hematological cancer cell lines at submicromolar concentrations. In both types of cell lines, compound 2 inhibited phosphorylation of Pim signaling substrates and cell-cycle progression and induced apoptosis.
Conclusion:
We identified a pan-Pim kinases inhibitor, compound 2, with a rhodanine-benzoimidazole structure. Our data suggest that compound 2 can serve as a lead to novel anticancer agents, effective in the treatment of both solid carcinomas and hematological malignancies.
Insights
Researchers developed a new compound that inhibits Pim kinases, showing potent anti-cancer effects against solid and blood cancers by stopping cell growth and causing cell death.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Serine/threonine Pim kinases are frequently overexpressed in various cancers.
- Pim kinases play a crucial role in cell-cycle progression and survival.
- Targeting Pim kinases offers a potential strategy for cancer therapy.
Purpose of the Study:
- To discover a novel pan-Pim kinases inhibitor.
- To identify a compound with potent anti-proliferative activity against cancer cell lines.
- To develop lead compounds for novel anticancer agents.
Main Methods:
- Screening of small molecule compounds for Pim-1 kinase inhibition.
- Structure-based drug design and optimization using docking analysis.
- In vitro kinase inhibition assays, cell proliferation assays, western blotting, FACS, and apoptosis assays.
Main Results:
- A potent and selective pan-Pim kinases inhibitor, compound 2 (rhodanine-benzoimidazole structure), was identified.
- Compound 2 demonstrated significant anti-proliferative effects in solid and hematological cancer cell lines at submicromolar concentrations.
- Compound 2 inhibited Pim signaling, cell-cycle progression, and induced apoptosis in cancer cells.
Conclusions:
- Compound 2 is a promising lead for the development of novel anticancer therapeutics.
- The identified inhibitor is effective against both solid carcinomas and hematological malignancies.
- Targeting Pim kinases with compound 2 represents a viable strategy for cancer treatment.
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