6C2R

Aurora A ligand complex

Summary for 6C2R

• Entry DOI: 10.2210/pdb6c2r/pdb
• Descriptor: Aurora kinase A, SULFATE ION, (2R,4R)-1-[(3-chloro-2-fluorophenyl)methyl]-4-({3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl}methyl)-2-methylpiperidine-4-carboxylic acid, ... (4 entities in total)
• Functional Keywords: protein kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32218.28

Authors

Antonysamy, S.,Pustilnik, A.,Manglicmot, D.,Froning, K.,Weichert, K.,Wasserman, S. (deposition date: 2018-01-08, release date: 2019-01-23, Last modification date: 2024-03-13)

Primary citation

Gong, X.,Du, J.,Parsons, S.H.,Merzoug, F.F.,Webster, Y.,Iversen, P.W.,Chio, L.C.,Van Horn, R.D.,Lin, X.,Blosser, W.,Han, B.,Jin, S.,Yao, S.,Bian, H.,Ficklin, C.,Fan, L.,Kapoor, A.,Antonysamy, S.,Mc Nulty, A.M.,Froning, K.,Manglicmot, D.,Pustilnik, A.,Weichert, K.,Wasserman, S.R.,Dowless, M.,Marugan, C.,Baquero, C.,Lallena, M.J.,Eastman, S.W.,Hui, Y.H.,Dieter, M.Z.,Doman, T.,Chu, S.,Qian, H.R.,Ye, X.S.,Barda, D.A.,Plowman, G.D.,Reinhard, C.,Campbell, R.M.,Henry, J.R.,Buchanan, S.G.
Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of theRB1Tumor Suppressor Gene.
Cancer Discov, 9:248-263, 2019

PubMed Abstract: Loss-of-function mutations in the retinoblastoma gene are common in several treatment-refractory cancers such as small-cell lung cancer and triple-negative breast cancer. To identify drugs synthetic lethal with mutation ( ), we tested 36 cell-cycle inhibitors using a cancer cell panel profiling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against cancer cells and leads to durable regression of tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identification of a synthetic lethal interaction between and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-deficient malignancies, including patients progressing on CDK4/6 inhibitors...

PubMed: 30373917
DOI: 10.1158/2159-8290.CD-18-0469

Experimental method

X-RAY DIFFRACTION (1.96 Å)