Discovery of potent KIFC1 inhibitors using a method of integrated high-throughput synthesis and screening.

Abstract

KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies.

• Authors: Bin Yang, Michelle L Lamb, Tao Zhang, Edward J Hennessy, Gurmit Grewal, Li Sha, Mark Zambrowski, Michael H Block, James E Dowling, Nancy Su, Jiaquan Wu, Tracy Deegan, Keith Mikule, Wenxian Wang, Rüdiger Kaspera, Claudio Chuaqui, Huawei Chen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 23 Pg. 9958-70 (Dec 11 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25458601 (Publication Type: Journal Article)

Chemical References

• 5-methyl-N-(1-oxo-1-(pyrrolidin-3-ylamino)-3-(6-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)propan-2-yl)-4-propylthiophene-2-carboxamide
• KIFC1 protein, human
• Pyridines
• Phenylalanine
• Kinesins
• Alanine

Topics

• Alanine (analogs & derivatives, chemical synthesis, pharmacology)
• Animals
• HeLa Cells
• High-Throughput Screening Assays (methods)
• Humans
• Inhibitory Concentration 50
• Kinesins (antagonists & inhibitors)
• Mice
• Phenylalanine (analogs & derivatives)
• Pyridines (chemical synthesis, pharmacology)
• Rats
• Structure-Activity Relationship