Bone-Targeted 2,6,9-Trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases

Wang, Yihan; Metcalf, Chester A.; Shakespeare, William C.; Rajeswari, S.; Keenan, Terence P.; Bohacek, Regine S.; Schravendijk, Marie Rose van; Violette, Shiela M.; Narula, Surinder S.; Dalgarno, David C.; Haraldson, Chad; Keats, Jeffrey A.; Liou, Shuenn; Mani, Ukti N.; Pradeepan, Selvi; Ram, Mary K.; Adams, Susan; Weigele, Manfred; Sawyer, Tomi K.

doi:10.1016/s0960-894x(03)00648-6

Cited by 50 publications

(9 citation statements)

References 23 publications

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“…This inhibitor was first identified as a potent inhibitor for CDKs (Dalgarno et al., 2006; Giocanti et al., 1999) and was subsequently also described as an Src inhibitor (Wang et al., 2003). In PAK4 and PAK5, the inhibitor interacted with conserved active site residues.…”

Section: Resultsmentioning

confidence: 99%

Crystal Structures of the p21-Activated Kinases PAK4, PAK5, and PAK6 Reveal Catalytic Domain Plasticity of Active Group II PAKs

et al. 2007

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Summaryp21-activated kinases have been classified into two groups based on their domain architecture. Group II PAKs (PAK4–6) regulate a wide variety of cellular functions, and PAK deregulation has been linked to tumor development. Structural comparison of five high-resolution structures comprising all active, monophosphorylated group II catalytic domains revealed a surprising degree of domain plasticity, including a number of catalytically productive and nonproductive conformers. Rearrangements of helix αC, a key regulatory element of kinase function, resulted in an additional helical turn at the αC N terminus and a distortion of its C terminus, a movement hitherto unseen in protein kinases. The observed structural changes led to the formation of interactions between conserved residues that structurally link the glycine-rich loop, αC, and the activation segment and firmly anchor αC in an active conformation. Inhibitor screening identified six potent PAK inhibitors from which a tri-substituted purine inhibitor was cocrystallized with PAK4 and PAK5.

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Section: Resultsmentioning

confidence: 99%

Crystal Structures of the p21-Activated Kinases PAK4, PAK5, and PAK6 Reveal Catalytic Domain Plasticity of Active Group II PAKs

et al. 2007

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“…For example, we performed a preliminary screening of compounds 7a-j towards several protein kinases in order to find possible targets. Due to the structural analogy to known CDK inhibitors [27][28][29][30], the screening included CDK2/cyclin E, CDK9/cyclin T, PKN3, and Abl kinases, but these compounds did not show any activity up to a dose of 10 µ M (data not shown). In addition, we performed preliminary experiments with one of the most potent compounds also in the MCF7 cell line, which served as a model of solid cancer.…”

Section: Search Of Molecular Targetsmentioning

confidence: 99%

“…Some purine-based compounds which target these proteins have been synthesized, and considering the essential role of some kinases in the regulation of the cell cycle or proliferation signaling, have transformed these compounds into new and potential anticancer agents [17,27,28]. Some examples of 2,6,9-trisubstituted purine with these biological properties are compounds III [29] and IV [30] (Figure 2). In this sense, III is a potent tyrosine kinase inhibitor that elicits inhibition on cyclin-dependent kinases (CDK), Src, and VEGFR2, and all of these targets are related to cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Salas

Zárate

Kryštof

et al. 2019

IJMS

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We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

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“…Das Enzym nimmt im Komplex mit 6 eine andere Gesamtkonformation an (offene Konformation,blaues Band) als im Komplex mit ZOL und IPP (geschlossene Konformation,g raues Band). [16,17] Cathepsin K [18] ," Colony-stimulating-factor-1"-Rezeptor (CSF-1R), selektiven Androgenrezeptormodulatoren (SARMs), selektiven Östrogenrezeptormodulatoren (SERMs) oder Prostaglandin-E2-Konjugaten. [19] …”

Section: Abbildung 2 Kristallstruktur Des Binären Komplexes Von Fppsunclassified

Gezielte Anreicherung von Wirkstoffen am Knochen am Beispiel von allosterischen FPPS‐Inhibitoren

et al. 2015

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Bone-Targeted 2,6,9-Trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases

Cited by 50 publications

References 23 publications

Crystal Structures of the p21-Activated Kinases PAK4, PAK5, and PAK6 Reveal Catalytic Domain Plasticity of Active Group II PAKs

Crystal Structures of the p21-Activated Kinases PAK4, PAK5, and PAK6 Reveal Catalytic Domain Plasticity of Active Group II PAKs

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays

Gezielte Anreicherung von Wirkstoffen am Knochen am Beispiel von allosterischen FPPS‐Inhibitoren

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