Imidazo[4,5-<i>b</i>]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidate

Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; Brandon, Alexis de Haven; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward

doi:10.1021/jm100262j

Cited by 81 publications

(112 citation statements)

References 37 publications

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“…Furthermore, as shown in (20,21). In contrast, most Aurora-A inhibitors, such as CCT137690, do not substantially affect the structure of the protein (24). There is no available crystal structure of MLN8237 bound to Aurora-A, but the chemical structures of MLN8054 and MLN8237 are almost identical, and it is likely that MLN8237 induces a similar conformation in Aurora-A.…”

Section: Resultsmentioning

confidence: 96%

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Richards

Burgess

Poon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Myc family proteins promote cancer by inducing widespread changes in gene expression. Their rapid turnover by the ubiquitin–proteasome pathway is regulated through phosphorylation of Myc Box I and ubiquitination by the E3 ubiquitin ligase SCFFbxW7. However, N-Myc protein (the product of theMYCNoncogene) is stabilized in neuroblastoma by the protein kinase Aurora-A in a manner that is sensitive to certain Aurora-A–selective inhibitors. Here we identify a direct interaction between the catalytic domain of Aurora-A and a site flanking Myc Box I that also binds SCFFbxW7. We determined the crystal structure of the complex between Aurora-A and this region of N-Myc to 1.72-Å resolution. The structure indicates that the conformation of Aurora-A induced by compounds such as alisertib and CD532 is not compatible with the binding of N-Myc, explaining the activity of these compounds in neuroblastoma cells and providing a rational basis for the design of cancer therapeutics optimized for destabilization of the complex. We also propose a model for the stabilization mechanism in which binding to Aurora-A alters how N-Myc interacts with SCFFbxW7to disfavor the generation of Lys48-linked polyubiquitin chains.

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Section: Resultsmentioning

confidence: 96%

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Richards

Burgess

Poon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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136

145

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“…The yellow solution was stirred for 3 h before the mixture was concentrated in vacuo. The resulting crude product was purified by Biotage column chromatography (cyclohexane/EtOAc 5:1 to 1:1) to give 5-bromo-4-chloropyridin-2-amine 38 as a yellow solid (10.0 g, 83% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 8.16 (s, 1H), 6.62 (s, 1H), 4.57 (s, 2H); LC–MS (method C, ESI, m / z ) t R = 2.04 min, 207/209/211 (M + H) + .…”

Section: Methodsmentioning

confidence: 99%

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

et al. 2016

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The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.

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“…Replacement of the bridging nitrogen atom of an atypical antipsychotic clozapine with an oxygen atom in loxapine or with sulfur in quetiapine ( Figure 2) prevents bioactivation of the dibenzoxazepine moiety and results in a drug with improved safety profile (Uetrecht et al, 1997). Furthermore, examples where resolution of RM liability (while maintaining primary pharmacology and disposition attributes) occurred through rational medicinal chemistry design has been considered to be a success story have also been presented (Bavetsias et al, 2010;Cox et al, 2010;Crawford et al, 2012;Finlay et al, 2012;Hartz et al, 2009;Kalgutkar et al, 2010Kalgutkar et al, , 2011Kalgutkar et al, , 2013Sarabu et al, 2012;Subramanian et al, 2010;Zhang et al, 2008). For instance, fluorofelbamate was specifically designed to eliminate the RM liability of felbamate on the basis of its bioactivation mechanism ( Figure 3) (Roecklein et al, 2007).…”

Section: Interpretation Of a ''Positive Signal'' (Detection Of A Gsh mentioning

confidence: 99%

Practical approaches to resolving reactive metabolite liabilities in early discovery

Dalvie

Kalgutkar

Chen

2014

Drug Metabolism Reviews

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Idiosyncratic toxicity is one of the principal causes for withdrawal of marketed drugs after launch. Circumstantial evidence suggests that several drug-induced adverse effects are a result of transformation of a drug to electrophilic reactive metabolites (RMs) that can covalently bind to vital macromolecules in the body. Strategies have been implemented in early discovery to examine (and minimize) the formation of RMs. A common technique involves incubation of a new chemical entity with NADPH-supplemented human liver microsomes (HLMs) in the presence of soft nucleophilic trapping agents, such as glutathione (GSH) or N-acetylcysteine (NAC). Advances in mass spectrometry and the advent of very sensitive mass spectrometers ensure facile identification of the resulting GSH or NAC adducts of the reactive species. Detection of sulfhydryl conjugates in in vitro incubations, however, raise more questions regarding the path forward for RM-positive drug candidates. One approach that can assist in mitigating RM formation is assessment of their total body burden. Computation of dose using in vitro intrinsic clearance (Clint), potency data (Ceff) and the fractional contribution of RM pathway (frm), can provide an initial read of the daily burden of RM. This overview attempts to provide practical ways of assessing these factors and assist in putting the risk of RM formation into perspective.

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Imidazo[4,5-b]pyridine Derivatives As Inhibitors of Aurora Kinases: Lead Optimization Studies toward the Identification of an Orally Bioavailable Preclinical Development Candidate

Cited by 81 publications

References 37 publications

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Structural basis of N-Myc binding by Aurora-A and its destabilization by kinase inhibitors

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

Practical approaches to resolving reactive metabolite liabilities in early discovery

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