title: Novel pyrrolopyrimidines as Mps1/TTK kinase inhibitors for breast cancer.
abstract: New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC50values ranging from 0.05 to 1.0μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC50values from 0.356μM to 0.809μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13, significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yasuro
authors.initials: Y
authors.lastname: Sugimoto
authors.affiliation: Department of Molecular Genetics, College of Arts & Sciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Dwitiya B
authors.initials: DB
authors.lastname: Sawant
authors.affiliation: Department of Molecular Genetics, College of Arts & Sciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Fisk
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Liguang
authors.initials: L
authors.lastname: Mao
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Somsundaram
authors.initials: S
authors.lastname: Chettiar
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Darby
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Brueggemeier.1@osu.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Brueggemeier
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: Breast cancer; Centrosome amplification; Mps-1; Pyrrolopyrimidine analogues; Spindle checkpoint kinases; TTK