title: Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen.
abstract: The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anticancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a subseries with selectivity toward Aurora A. A direct comparison of biochemical and cellular profiles with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora-dependent functions.
authors: Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
authors: Nicholas
authors: N
authors: Kwiatkowski
authors: Xianming
authors: X
authors: Deng
authors: Jinhua
authors: J
authors: Wang
authors: Li
authors: L
authors: Tan
authors: Fabrizio
authors: F
authors: Villa
authors: Stefano
authors: S
authors: Santaguida
authors: Hsiao-Chun
authors: HC
authors: Huang
authors: Tim
authors: T
authors: Mitchison
authors: Andrea
authors: A
authors: Musacchio
authors: Nathanael
authors: N
authors: Gray
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000737:chemistry / Q000494:pharmacology*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008958:Models, Molecular; D010755:Organophosphates / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001552:Benzazepines; D007527:Isoenzymes; D010755:Organophosphates; D017239:Paclitaxel; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D011799:Quinazolines; C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; C518940:MLN8054; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C576921:AURKB protein, human