The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-<i>a</i>]pyridines

Hamdouchi, Chafiq; Keyser, Heather; Collins, Elizabeth; Jaramillo, Carlos; Diego, J. Eugenio de; Spencer, Charles D.; Dempsey, Jack; Anderson, Bryan D.; Leggett, Tillie; Stamm, Nancy B.; Schultz, Richard M.; Watkins, Scott A.; Cocke, Kim; Lemke, Stephanie; Burke, Thomas G.; Beckmann, Richard P.; Dixon, Jeffrey T.; Gurganus, Thomas M.; Rankl, Nancy B.; Houck, Keith A.; Zhang, Faming; Vieth, Michał; Espinosa, Juan F.; Timm, David E.; Campbell, Robert M.; Patel, Bharvin K.R.; Brooks, Harold B.

doi:10.1158/1535-7163.1.3.1

Cited by 13 publications

(5 citation statements)

References 44 publications

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“…Besides, several compounds with a variety of heterocyclic cores (Figure ) were identified as potent inhibitors of CDK2 by using bioisosterism as a rational tool to design new scaffolds from the purine core. These includes pyrazolo[3,4- d ]pyrimidines, , pyrazolo[1,5- a ]pyrimidines, , pyrazolo[1,5- a ]-1,3,5-triazines, , pyrazolo[3,4- b ]pyridines, imidazo[2,1- f ]-1,2,4-triazines, , imidazo[1,2- a ]pyrazines, imidazo[4,5- b ]pyridines, imidazo[1,2- a ]pyridine, − imidazo[1,2- b ]pyridazine, and triazolo[1,5- a ]pyrimidines …”

Section: Cdk2 Inhibitors In Drug Developmentmentioning

confidence: 99%

Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update

et al. 2018

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Cyclin-dependent kinase 2 (CDK2) drives the progression of cells into the S- and M-phases of the cell cycle. CDK2 activity is largely dispensable for normal development, but it is critically associated with tumor growth in multiple cancer types. Although the role of CDK2 in tumorigenesis has been controversial, emerging evidence proposes that selective CDK2 inhibition may provide a therapeutic benefit against certain tumors, and it continues to appeal as a strategy to exploit in anticancer drug development. Several small-molecule CDK2 inhibitors have progressed to the clinical trials. However, a CDK2-selective inhibitor is yet to be discovered. Here, we discuss the latest understandings of the role of CDK2 in normal and cancer cells, review the core pharmacophores used to target CDK2, and outline strategies for the rational design of CDK2 inhibitors. We attempt to provide an outlook on how CDK2-selective inhibitors may open new avenues for cancer therapy.

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Section: Cdk2 Inhibitors In Drug Developmentmentioning

confidence: 99%

Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update

et al. 2018

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“…This structure is somewhat unusual, since the free aromatic amine is on the solvent side. 55 Isoquinolines. There are several isoquinoline structures (Table 3, 23) bound to four kinases (CK17, PKA, PRKACA, and ROCK) in the PDB.…”

Section: Imidazo[12-a]pyridinementioning

confidence: 99%

“…Here, the imidazole N3 is hydrogen-bonded to gk+3 along with the NH 2 group adjacent to it. This structure is somewhat unusual, since the free aromatic amine is on the solvent side …”

Section: Binding Modes Of Other Hinge Binding Scaffold Typesmentioning

confidence: 99%

Knowledge Based Prediction of Ligand Binding Modes and Rational Inhibitor Design for Kinase Drug Discovery

Ghose¹,

et al. 2008

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“…Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells . Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies, and there is a continuing interest in this field . In a previous paper we described the discovery and the lead finding process of a new class of 3-aminopyrazole CDK2/cyclin A inhibitors .…”

Section: Introductionmentioning

confidence: 99%

3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 2. Lead Optimization

et al. 2005

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Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.

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The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines

Cited by 13 publications

References 44 publications

Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update

Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update

Knowledge Based Prediction of Ligand Binding Modes and Rational Inhibitor Design for Kinase Drug Discovery

3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 2. Lead Optimization

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