title: Design, synthesis, and biological evaluation of pyrazolopyrimidine-sulfonamides as potent multiple-mitotic kinase (MMK) inhibitors (part I).
abstract: A novel class of pyrazolopyrimidine-sulfonamides was discovered as selective dual inhibitors of aurora kinase A (AKA) and cyclin-dependent kinase 1 (CDK1). These inhibitors were originally designed based on an early lead (compound I). SAR development has led to the discovery of potent inhibitors with single digit nM IC(50)s towards both AKA and CDK1. An exemplary compound 1a has demonstrated good efficacy in an HCT116 colon cancer xenograft model.
authors.affiliation: Biogen Idec, 5200 Research Place, San Diego, CA 92122, United States. lin.zhang.ge@sbcglobal.net
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: Jer-Hong
authors.initials: JH
authors.lastname: Chong
authors.forename: Angela
authors.initials: A
authors.lastname: Cesena
authors.forename: Betty Y Y
authors.initials: BY
authors.lastname: Tam
authors.forename: Charles
authors.initials: C
authors.lastname: Gilson
authors.forename: Christina
authors.initials: C
authors.lastname: Boykin
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.forename: Dikran
authors.initials: D
authors.lastname: Aivazian
authors.forename: Doug
authors.initials: D
authors.lastname: Marcotte
authors.forename: Guangqing
authors.initials: G
authors.lastname: Xiao
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Brazidec
authors.forename: Jinhua
authors.initials: J
authors.lastname: Piao
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Kevin
authors.initials: K
authors.lastname: Hong
authors.forename: Khang
authors.initials: K
authors.lastname: Vu
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.forename: Liang-Shang
authors.initials: LS
authors.lastname: Gan
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.forename: Leona
authors.initials: L
authors.lastname: Ling
authors.forename: Min
authors.initials: M
authors.lastname: Teng
authors.forename: Mitchell
authors.initials: M
authors.lastname: Reff
authors.forename: Nicole
authors.initials: N
authors.lastname: Takeda
authors.forename: Noel
authors.initials: N
authors.lastname: Timple
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Ron
authors.initials: R
authors.lastname: Morena
authors.forename: Samina
authors.initials: S
authors.lastname: Khan
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhao
authors.forename: Tony
authors.initials: T
authors.lastname: Li
authors.forename: Wen-Cherng
authors.initials: WC
authors.lastname: Lee
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Taveras
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051638:Ether-A-Go-Go Potassium Channels; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase