Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer’s disease

Helal, Christopher J.; Sanner, Mark A.; Cooper, Christopher B.; Gant, Thomas G.; Adam, Mavis; Lucas, John C.; Kang, Zhijun; Kupchinsky, Stanley; Ahlijanian, Michael K.; Tate, Bonnie F.; Menniti, Frank S.; Kelly, Kristin N.; Peterson, Marcia

doi:10.1016/j.bmcl.2004.09.006

Cited by 95 publications

(61 citation statements)

References 7 publications

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“…5) is an inhibitor selective for CDK5 (IC 50 = 64 nM) and CDK2 (IC 50 = 98 nM). It is an ATP competitive CDK inhibitor discovered by molecular modeling studies (Helal et al 2004). Although it deWnitely needs further validations and preclinical studies, this compound is already available commercially.…”

Section: Selective Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

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Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in diVerent human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer's, Parkinson's diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the speciWc purpose of their research. For this purpose, the targets, commercial availability and IC 50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

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Section: Selective Inhibitorsmentioning

confidence: 99%

The CDK inhibitors in cancer research and therapy

Cicenas

Valius²

2011

J Cancer Res Clin Oncol

220

176

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“…1) are being developed as an inhibitor of glycogen synthase kinase-3b as its dysregulation is implicated in certain psychiatric and neurodegenerative diseases [31,32] and these agents are being considered as a novel strategy to treat PD [33]. Also, a series of aryl/heteroaryl ureas bearing thiazole moiety have emerged as a potent and selective inhibitors of cyclin dependent kinases for the treatment of Alzheimer's disease and other neurodegenerative disorders [34].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice

Azam¹,

Alkskas²,

Ahmed

2009

European Journal of Medicinal Chemistry

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“…Therefore, the CDK5/p25 complex has become an attractive pharmacological target. The design of novel CDK5/p25 inhibitors attracts much interest in recent years [1,[10][11][12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

Keke

Wang

Yang

et al. 2016

Journal of Molecular Graphics and Modelling

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Roscovitine derivatives are potent inhibitors of cyclin-dependent kinase 5 (CDK5), but they exhibit different activities, which has not been understood clearly up to now. On the other hand, the task of drug design is difficult because of the fuzzy binding mechanism. In this context, the methods of molecular docking, molecular dynamics (MD) simulation, and binding free energy analysis are applied to investigate and reveal the detailed binding mechanism of four roscovitine derivatives with CDK5. The electrostatic and van der Waals interactions of the four inhibitors with CDK5 are analyzed and discussed. The calculated binding free energies in terms of MM-PBSA method are consistent with experimental ranking of inhibitor effectiveness for the four inhibitors. The hydrogen bonds of the inhibitors with Cys83 and Lys33 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the pivotal contacts with Ile10 and Leu133 have larger contributions to the binding free energy and play critical roles in distinguishing the variant bioactivity of four inhibitors. In terms of binding mechanism of the four inhibitors with CDK5 and energy contribution of fragments of each inhibitor, two new CDK5 inhibitors are designed and have stronger inhibitory potency.

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Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer’s disease

Cited by 95 publications

References 7 publications

The CDK inhibitors in cancer research and therapy

The CDK inhibitors in cancer research and therapy

Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice

Binding mechanism of CDK5 with roscovitine derivatives based on molecular dynamics simulations and MM/PBSA methods

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