Discovery of a potent and selective Aurora kinase inhibitor

Oslob, Johan D.; Romanowski, M.J.; Allen, Darin; Baskaran, Sundarababu; Bui, Minna; Elling, R.A.; Flanagan, W. Michael; Fung, Amy; Hanan, Emily J.; Harris, Shannon O.; Heumann, Stacey A.; Hoch, Ute; Jacobs, J. W.; Lam, Joni; Lawrence, Chris E.; McDowell, Robert S.; Nannini, Michelle; Wang, Shen; Silverman, Jeffrey A.; Sopko, Michelle M.; Tangonan, Bradley T.; Teague, Juli; Yoburn, Josh C.; Yu, Chul H.; Zhong, Min; Zimmerman, Kristin; O’Brien, Tom; Lew, Willard

doi:10.1016/j.bmcl.2008.07.073

Cited by 97 publications

(64 citation statements)

References 19 publications

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“…We have previously described SNS-314, a selective and potent pan-Aurora inhibitor currently in phase 1 clinical trials for the treatment of patients with advanced solid tumors (25,26). The cellular phenotypes of most pan-Aurora inhibitors (including SNS-314) are dominated by the effects resulting from Aurora-B inhibition, which leads to multiple defects in mitosis, including aberrant centrosome duplication, disruption of the spindle checkpoint, and inhibition of cytokinesis, which in turn lead to endoreduplication, polyploidy, and cytostasis or cell death (22).…”

Section: Introductionmentioning

confidence: 99%

The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model

VanderPorten

Taverna

Hogan

et al. 2009

Molecular Cancer Therapeutics

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Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxinmediated mitotic catastrophe and cell death. [Mol Cancer Ther 2009;8(4):930-9]

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Section: Introductionmentioning

confidence: 99%

The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model

VanderPorten

Taverna

Hogan

et al. 2009

Molecular Cancer Therapeutics

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“…FP). Related to this is the receiver operating characteristic [21,38,39] (roc) curve; a roc curve is a plot of Se (the true positive rate) versus 1-Sp (the false positive rate). Such plots can be used to study the ability of screening protocols to distinguish active from inactive compounds.…”

Section: Analysis Of Screeningmentioning

confidence: 99%

“…Indeed, many Type I inhibitors appear to have a very Type II-like chemical scaffold. For example, Type II inhibitors such as imatinib 1 [16], BIRB796 2 [11], sorafenib 3 [17] and nilotinib 4 [18] bear considerable resemblance to the Type I inhibitors such as an inhibitor of Lck protein kinase 5 [19], dasatinib 6 [20], or an inhibitor of Aurora A 7 (Scheme 1) [21]. This makes it difficult to distinguish Type I from Type II ligands; however, we note some recent success in identifying Type II inhibitors using a receptor-based approach by Kurafeva and Abagyan [6], where DFG-in kinase structures are Fig.…”

Section: Introductionmentioning

confidence: 99%

Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

Mucs

Bryce

Bonnet

2011

J Comput Aided Mol Des

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The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 ± 8° and twist of 78 ± 8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.

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“…A recent paper discusses the discovery and development of SNS-314 which is in Phase I clinical trials, starting from a lead identified by screening the in-house compound library [100]. SNS-314 inhibits aurora-A, aurora-B and aurora-C with an IC 50 value of 9 nM, 31 nM and 3.4 nM respectively [100,101].…”

Section: Sns-314 Developed By Sunesismentioning

confidence: 99%