Design, Synthesis, and Structure−Activity Relationship of 6-Alkynylpyrimidines as Potent Adenosine Kinase Inhibitors

Gomtsyan, Arthur; DiDomenico, Stanley; Lee, Chih‐Hung; Matulenko, Mark A.; Kim, Ki‐Hyun; Kowaluk, Elizabeth A.; Wismer, Carol T.; Mikusa, Joe; H, Yu; Kohlhaas, Kathy L.; Jarvis, Michael F.; Bhagwat, Shripad S.

doi:10.1021/jm020049a

Cited by 54 publications

(35 citation statements)

References 14 publications

(22 reference statements)

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“…Nonnucleoside Adenosine Kinase Inhibitors. Nonnucleoside ADK inhibitors lack ribose or cyclopentane rings and are either built on pyridopyrimidine cores or on alkynylpyrimidine cores, which were shown to reduce pain and inflammation in a variety of animal models (Cowart et al, 2001;Zheng et al, 2001;Gfesser et al, 2003;Gomtsyan et al, 2002. A virtual screening approach led to the discovery of a different class of nonnucleoside ADK inhibitors based on 2-aryl oxazolo-pyrimidines, which were further optimized to yield a variety of highly potent derivatives (Fig.…”

Section: Pharmacologymentioning

confidence: 99%

Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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Section: Pharmacologymentioning

confidence: 99%

Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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“…Inhibition of its activity enhances the release of adenosine from cells, and extracellular adenosine is known to act as a neuromodulator with potent anti-nociceptive and anti-inflammatory actions. Therefore, inhibition of AK activity is proposed as a therapeutic strategy for the treatment of pain, and inflammation and several potent inhibitors of AK activity have been reported (25)(26)(27). To analyze AK binding to BisIII beads, a myc-tagged version of AK was transiently expressed in COS-7 cells.…”

Section: Generation Of Pkc Inhibitor Affinitymentioning

confidence: 99%

Proteome-wide Identification of Cellular Targets Affected by Bisindolylmaleimide-type Protein Kinase C Inhibitors

Brehmer

Godl

Zech

et al. 2004

Molecular & Cellular Proteomics

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Bisindolylmaleimide compounds such as GF109203X are potent inhibitors of protein kinase C (PKC) activity. Although bisindolylmaleimides are not entirely selective for PKC and are known to inhibit a few other protein kinases, these reagents have been extensively used to study the functional roles of PKC family enzymes in cellular signal transduction for more than a decade. Here, we establish a proteomics approach to gain further insights into the cellular effects of this compound class. Functional immobilization of suitable bisindolylmaleimide analogues in combination with the specific purification of cellular binding proteins by affinity chromatography led to the identification of several known and previously unknown enzyme targets. Subsequent in vitro binding and activity assays confirmed the protein kinases Ste20-related kinase and cyclin-dependent kinase 2 (CDK2) and the non-protein kinases adenosine kinase and quinone reductase type 2 as novel targets of bisindolylmaleimide inhibitors. As observed specifically for CDK2, minor chemical variation of the ligand by immobilizing the closely related bisindolylmaleimides III, VIII, and X dramatically affected target binding. These observed changes in affinity correlated with both the measured IC 50 values for in vitro CDK2 inhibition and results from molecular docking into the CDK2 crystal structure. Moreover, the conditions for affinity purification could be adapted in a way that immobilized bisindolylmaleimide III selectively interacted with either PKC␣ or ribosomal S6 protein kinase 1 only after activation of these kinases. Thus, we have established an efficient technique for the rapid identification of cellular bisindolylmaleimide targets and further demonstrate the comparative selectivity profiling of closely related kinase inhibitors within a cellular proteome. Molecular & Cellular Proteomics 3:490 -500, 2004.

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“…Reduction of the formyl group in compound 1 [7] with NaBH 4 in MeOH furnished the corresponding alcohol derivatives 2 in 92% yields. Compound 2 was treated with SOCl 2 to lead to chloromethylpyrimidine 3, which without further purification, reacted with various racemic amino acid esters [8] to provide precursors 4 in high overall yields (Table 1).…”

Section: Resultsmentioning

confidence: 99%