Scaffold hopping identifies 6,8-disubstituted purines as novel anaplastic lymphoma kinase inhibitors (original) (raw)
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Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor
Nature Structural Biology, 2002
Iterative structure-based design was used to optimize the ATPcompetitive inhibition of CDK1 and CDK2 by O 6 -cyclohexylmethylguanines, resulting in O 6 -cyclohexylmethyl-2-(4′sulfamoylanilino)purine. The new inhibitor is 1,000-fold more potent than the parent compound (K i values for CDK1 = 9 nM and CDK2 = 6 nM versus 5,000 nM and 12,000 nM, respectively, for O 6 -cyclohexylmethylguanine). The increased potency arises primarily from the formation of two additional hydrogen bonds between the inhibitor and Asp 86 of CDK2, which facilitate optimum hydrophobic packing of the anilino group with the specificity surface of CDK2. Cellular studies with O 6 -cyclohexylmethyl-2-(4′sulfamoylanilino) purine demonstrated inhibition of MCF-7 cell growth and target protein phosphorylation, consistent with CDK1 and CDK2 inhibition. The work represents the first successful iterative synthesis of a potent CDK inhibitor based on the structure of fully activated CDK2-cyclin A. Furthermore, the potency of O 6 -cyclohexylmethyl-2-(4′-sulfamoylanilino)purine was both predicted and fully rationalized on the basis of protein-ligand interactions.
Pharmaceutics
We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 μM for BTK) and 5b (IC50 = 0.38 μM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore,...
2,6,8,9-Tetrasubstituted Purines as New CDK1 Inhibitors
Bioorganic & Medicinal Chemistry Letters, 2003
Purine inhibitors of cyclin-dependent kinases attract attention as potential anticancer drugs because their first representative roscovitine recently entered clinical trials. Although well described in terms of structure-activity relationships, we still present here a novel modification of the purine scaffold influencing their inhibitory properties. The introduced C-8 substituents, however, lowered the CDK inhibitory activity of roscovitine, whereas the antiproliferative potential of several derivatives remained high.
The purines: Potent and versatile small molecule inhibitors and modulators of key biological targets
Bioorganic & Medicinal Chemistry, 2006
The goal of this review is to highlight the wide range of biological activities displayed by purines, with particular emphasis on new purine-based agents which find potential application as chemical-biology tools and/or therapeutic agents. The expanding interest in the biological properties of polyfunctionalized purine derivatives issues, in large part, from the development of rapid high-throughput screening essays for new protein targets, and the corresponding development of efficient synthetic methodology adapted to the construction of highly diverse purine libraries. Purine-based compounds have found new applications as inducers of interferon and lineage-committed cell dedifferentiation, agonists and antagonists of adenosine receptors, ligands of corticotropin-releasing hormone receptors, and as inhibitors of HSP90, Src kinase, p38a MAP kinase, sulfotransferases, phosphodiesterases, and Cdks. The scope of application of purines in biology is most certainly far from being exhausted. Testing purine derivatives against the multitude of biological targets for which small molecule probes have not yet been found should thus be a natural reflex.
Organic & Biomolecular Chemistry, 2015
A 18-member library of 6,8,9-poly-substituted purines was prepared from pyrimidines, primary alcohols, and N,N-dimethylamides under basic conditions via a novel one-pot synthetic pathway controlled by amide sizes and the novel analogues were tested against two leukemia cell lines: Jurkat (acute T cell leukemia) and K562 (chronic erythroleukemia) cells. Compounds having a benzoxy group at C6 position of the aromatic ring exhibited antiproliferative activity in Jurkat cells whereas all compounds induced a lower effect on K562 cells. Analysis of cell cycle, Annexin-V staining, and cleavage of initiator caspases assays showed that the active purine analogues induce cell death by apoptosis. Based on these results, a new purine derivative was synthesized, 6-benzyloxy-9-tert-butyl-8-phenyl-9H-purine (6d), which displayed the highest activity of the series against Jurkat cell lines. Finally, 33 P-radiolabeled kinase assays using 96 recombinant human kinases known to be involved in apoptotic events were performed. Just one of the kinases tested, DAPK-1, was inhibited 50% or more by the phenotypic hits at 10 µM, suggesting that the inhibition of this target could be responsible for the induction of cell death by apoptosis. In agreement with the phenotypic results, the most active antiproliferative agent, 6d, displayed also the lowest IC 50 value against recombinant DAPK1 (2.5 µM), further supporting the potential role of this protein on the observed functional response. DAPK-1 inhibition led by 6d together with its pro-apoptotic properties against the Jurkat line makes it an interesting candidate to further investigate the role of DAPK1 kinase in triggering apoptosis in cancer cells, a role which is attracting recent interest. † Electronic supplementary information (ESI) available: Experimental synthetic protocols and characterization data, including NMR data (1 H and 13 C) and mass spectrometry data (HRMS) of compounds. Raw data of the 33 P radiolabeled kinase assay containing the list of the 96 kinases was used for IC 50 _ DAPK1 graphs. See
Chemical Biology <html_ent glyph="@amp;" ascii="&"/> Drug Design, 2006
The majority of small-molecule Src inhibitors are targeted at the ATP-binding site of the catalytic domain of the kinase. A number of planar heteroaromatic small-molecule inhibitor templates have been exploited in the discovery of Src kinase inhibitors, thus purine, pyrrolopyrimidine, pyridopyrimidine, naphthyridone, quinazoline, and quinoline-based inhibitors have been reported (11). Despite this variety, structural information on SFKs complexed with synthetic inhibitors is limited. Structures of Hck and Lck kinases have been 46
Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors
Bioorganic & medicinal chemistry letters, 2016
We report on an extensive structure-activity relationship study of novel PI4K IIIβ inhibitors. The purine derivative of the potent screening hit T-00127-HEV1 has served as a suitable starting point for a thorough investigation of positions 8 and 2. While position 8 of the purine scaffold can only bear a small substituent to maintain the inhibitory activity, position 2 is opened for extensive modification and can accommodate even substituted phenyl rings without the loss of PI4K IIIβ inhibitory activity. These empirical observations nicely correlate with the results of our docking study, which suggests that position 2 directs towards solution and can provide the necessary space for the interaction with remote residues of the enzyme, whereas the cavity around position 8 is strictly limited. The obtained compounds have also been subjected to antiviral screening against a panel of (+)ssRNA viruses.