- Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family
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The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.
- Bataille, Carole J.R.,Brennan, Méabh B.,Byrne, Simon,Davies, Stephen G.,Durbin, Matthew,Fedorov, Oleg,Huber, Kilian V.M.,Jones, Alan M.,Knapp, Stefan,Liu, Gu,Nadali, Anna,Quevedo, Camilo E.,Russell, Angela J.,Walker, Roderick G.,Westwood, Robert,Wynne, Graham M.
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supporting information
p. 2657 - 2665
(2017/04/06)
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- Synthesis and in-vitro cytotoxicity of poly-functionalized 4-(2-arylthiazol-4-yl)-4H-chromenes
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A new series of 4-aryl-4H-chromenes bearing a 2-arylthiazol-4-yl moiety at the 4-position were prepared as potential cytotoxic agents. The in-vitro cytotoxic activity of the synthesized 4-aryl-4H-chromenes was investigated in comparison with etoposide, a well-known anticancer drug, using MTT colorimetric assay. Among them, the 2-(2-chlorophenyl)thiazol-4-yl analog 4b showed the most potent activity against nasopharyngeal epidermoid carcinoma KB, medulloblastoma DAOY, and astrocytoma 1321N1, and compound 4d bearing a 2-(4-chlorophenyl) thiazol-4-yl moiety at the 4-position of the chromene ring exhibited the best inhibitory activity against breast cancer cells MCF-7, lung cancer cells A549, and colon adenocarcinoma cells SW480 with IC50 values less than 5 μM. The ability of compound 4b to induce apoptosis was confirmed in a nuclear morphological assay by DAPI staining in the KB and MCF-7 cells.
- Mahmoodi, Majid,Aliabadi, Alireza,Emami, Saeed,Safavi, Maliheh,Rajabalian, Saeed,Mohagheghi, Mohammad-Ali,Khoshzaban, Ahad,Samzadeh-Kermani, Alireza,Lamei, Navid,Shafiee, Abbas,Foroumadi, Alireza
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p. 411 - 416
(2011/08/05)
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