Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors

Bowers, Simeon; Truong, Anh P.; Ye, Michael; Aubele, Danielle L.; Sealy, Jennifer M.; Neitz, R. Jeffrey; Hom, Roy K.; Chan, Wayman; Dappen, Michael S.; Galemmo, Robert A.; Konradi, Andrei W.; Sham, Hing L.; Zhu, Yong; Beroza, Paul; Tonn, George; Zhang, Heather; Hoffman, Joseph G.; Motter, Ruth; Fauss, Donald; Tanaka, Pearl; Bova, Michael P.; Zhao, Rongjun; Tam, Danny; Ruslim, Lany; Baker, Jeanne; Pandya, Deepal; Diep, Linnea; Fitzgerald, Kent; Artis, Dean R.; Anderson, John P.; Bergeron, Marcelle

doi:10.1016/j.bmcl.2013.02.065

Cited by 25 publications

(28 citation statements)

References 11 publications

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“…Despite its excellent potency and Plk-2/Plk-1 selectivity, with a measured log P = 3.3, compound 20 demonstrated only modest oxidative metabolic stability relative to 18 and 19. Given the measured log P for 20, it was not surprising to observe a decrease in aqueous solubility relative to 19. Surprisingly, a dramatic decrease in solubility for 21 was observed, despite its lower measured log P, concomitant with a loss in permeability.…”

Section: Resultsmentioning

confidence: 94%

“…In the context of the bicyclic pteridine core, these focused efforts produced advanced analogues, one of which was used to generate promising evidence of target engagement in vivo. [19] However, our experience with methodical derivatization at the 8-position of the pteridinone ring compelled a more radical approach to variation of this sector. This was attempted by surveying analogues that kept the same basic architecture as 9, but incorporated a fused cycloalkyl ring on the pteridinone core to provide 7,8-tricyclic pteridinone analogues ( Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…Our efforts resulted in two closely related series of compounds that have enabled in vivo studies yielding encouraging data, and a portion of the compounds derived from this work, resulting from a focused sub-series SAR expansion, have been described separately. [19]…”

Section: Introductionmentioning

confidence: 99%

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Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

et al. 2013

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Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

et al. 2013

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“…This has led to efforts to generate small molecule PLK inhibitors for potential therapeutic use (Bowers et al, 2013; Fitzgerald et al, 2013; Bergeron et al, 2014). The utility of such compounds, however, has been questioned by a recent study showing that Ser129 phosphorylation by PLK2 is required for autophagic degradation of α-synuclein (Oueslati et al, 2013).…”

Section: Kinases Mediating α-Synuclein S129 Phosphorylation In Pdmentioning

confidence: 99%

Parkinsonâ€™s disease-implicated kinases in the brain; insights into disease pathogenesis

Dzamko

Zhou

Huang

et al. 2014

Front. Mol. Neurosci.

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Substantial evidence implicates abnormal protein kinase function in various aspects of Parkinson’s disease (PD) etiology. Elevated phosphorylation of the PD-defining pathological protein, α-synuclein, correlates with its aggregation and toxic accumulation in neurons, whilst genetic missense mutations in the kinases PTEN-induced putative kinase 1 and leucine-rich repeat kinase 2, increase susceptibility to PD. Experimental evidence also links kinases of the phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways, amongst others, to PD. Understanding how the levels or activities of these enzymes or their substrates change in brain tissue in relation to pathological states can provide insight into disease pathogenesis. Moreover, understanding when and where kinase dysfunction occurs is important as modulation of some of these signaling pathways can potentially lead to PD therapeutics. This review will summarize what is currently known in regard to the expression of these PD-implicated kinases in pathological human postmortem brain tissue.

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“…Compound 7a was prepared by general procedure using pyrimidine 6a and triethylamine 5a on a 1.1 mmol scale (0.21 g, 91%) as a while solid. 1 Ethyl 2-(4-Morpholinyl)-6-propyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (8). Compound 8 was prepared by the literature procedure 25 using pyrimidine 5c and ethyl butyrylacetate in 0.8 mmol scale (0.20 g, 77%) as a light yellow solid.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Regioselective Control of the S_NAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

et al. 2015

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The SNAr reaction of 2,4-dichloropyrimidines, further substituted with an electron-withdrawing substituent at C-5, has selectivity for substitution at C-4. Here we report that tertiary amine nucleophiles show excellent C-2 selectivity. In situ N-dealkylation of an intermediate gives the product that formally corresponds to the reaction of a secondary amine nucleophile at C-2. This reaction is practical (fast under simple reaction conditions, with good generality for tertiary amine structure and moderate to excellent yields) and significantly expands access to pyrimidine structures.

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Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors

Cited by 25 publications

References 11 publications

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Parkinsonâ€™s disease-implicated kinases in the brain; insights into disease pathogenesis

Regioselective Control of the S_NAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

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Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors

Cited by 25 publications

References 11 publications

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain

Parkinsonâ€™s disease-implicated kinases in the brain; insights into disease pathogenesis

Regioselective Control of the SNAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles

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Product

Resources

About

Regioselective Control of the S_NAr Amination of 5-Substituted-2,4-Dichloropyrimidines Using Tertiary Amine Nucleophiles