title: Novel Mps1 kinase inhibitors: from purine to pyrrolopyrimidine and quinazoline leads.
abstract: Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties.
authors.affiliation: Medicinal Chemistry, Myrexis, Inc., 305 Chipeta Way, Salt Lake City, UT 84108, United States. Electronic address: mbursavich@envivopharma.com.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: David
authors.initials: D
authors.lastname: Dastrup
authors.forename: Mark
authors.initials: M
authors.lastname: Shenderovich
authors.forename: Kraig M
authors.initials: KM
authors.lastname: Yager
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cimbora
authors.forename: Brandi
authors.initials: B
authors.lastname: Williams
authors.forename: D Vijay
authors.initials: DV
authors.lastname: Kumar
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; C527741:pyrrolopyrimidine; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human; C030985:purine
keywords: Cancer; Conformational restriction; Mps1; Protein kinase inhibitors; Purines; Pyrrolopyrimidines; Quinazoline; Scaffold hopping; Structure-based design; TTK