Kenpaullone

Kenpaullone is a potent inhibitor of CDK1/cyclin B and GSK-3β, with IC50s of 0.4 μM and 23 nM, and also inhibits CDK2/cyclin A, CDK2/cyclin E, and CDK5/p25 with IC50s of 0.68 μM, 7.5 μM, 0.85 μM, respectively.

In Vitro:Kenpaullone shows much less effect on c-src (IC50, 15 μM), casein kinase 2 (IC50, 20 μM), erk 1 (IC50, 20 μM), and erk 2 (IC50, 9 μM). Kenpaullone acts by competitive inhibition of ATP binding, and the apparent Ki is 2.5 μM. Kenpaullone can inhibit the growth of tumor cells in culture (mean GI50, 43 μM) and causes altered cell cycle progression most clearly revealed under conditions of recovery from serum starvation[1]. Kenpaullone demonstrates a wide range of biological utility, extending from maintenance of pancreatic β cell survival and proliferation to the induction of apoptosis in cancer cells[2].

References:
[1]. Zaharevitz DW, et al. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res. 1999 Jun 1;59(11):2566-9. [2]. Lyssiotis CA, et al. Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):8912-7.

New thiophene analogues of kenpaullone: synthesis and biological evaluation in breast cancer cells.[Pubmed:16122578]

Eur J Med Chem. 2005 Aug;40(8):757-63.

Thieno analogues of Kenpaullone have been synthesized using an established method. We investigated the effect of five structural analogues of Kenpaullone on vincristine sensitive and resistant MCF7 (human mammary adenocarcinoma) cells. One analogue, 8-Bromo-6,11-dihydro-thieno-[3',2':2,3]azepino[4,5-b]indol-5(4H)-one (3a), showed an antiproliferative activity in the drug sensitive cell line that led to cell accumulation in G2/M phase. In addition, repression of cdk1, a G2/M transition key regulator, as well as induction of p21 were observed at the mRNA level. Programmed cell death (apoptosis) was induced in early time treatments and was accompanied by p53 mRNA induction. The antiproliferative and proapoptotic properties of 3a make this CDK inhibitor an interesting candidate for further investigations.

Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.[Pubmed:19447925]

Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):8912-7.

Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, Kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.

Cell cycle molecular targets in novel anticancer drug discovery.[Pubmed:10788588]

Curr Pharm Des. 2000 Mar;6(4):379-92.

A number of potential molecular targets for novel anticancer drug discovery have been identified in cell cycle control mechanisms. Prominent among these are the regulatory proteins, cyclins and their effector counterparts the cyclin dependent kinases (CDKs). Aberrant expression of these proteins, particularly cyclins involved in the G1 phase of the cell cycle, namely the D and E cyclins, has been associated with a variety of human cancers, including breast and colorectal cancer, B-lymphoma, prostate and non-small cell lung cancer. Inhibition of CDK kinase activity has turned out to be the most productive strategy for the discovery and design novel anticancer agents specifically targeting the cell cycle. Other potentially useful cell cycle areas for exploration include cyclin-CDK interactions, Cdc25 activation of cyclin-CDK complexes, ubiquitin-mediated proteolysis of cyclins, cell cycle check point kinases like Chk1, and recently identified oncogenic cell cycle-related aurora and polo-like kinases. Potent specific inhibitors have been identified that bind to the ATP site of CDKs, mainly cyclin B-CDK1, cyclin A-CDK2, and cyclin D-CDK4 complexes, and inhibit kinase activity. X-ray crystallographic data of CDKs, and their complexes with inhibitors have played a major role in the success of drug discovery efforts. Combinatorial chemistry, highthroughput screening, functional genomics and informatics have also contributed. CDK inhibitors currently under investigation include flavopiridol, olomoucine, roscovitine, puvalanol B, the dihydroindolo[3,2-d][1]benzazepinone Kenpaullone, indirubin-3 -monoxime and novel diaminothiazoles such as AG12275. The anticancer therapeutic potential of CDK inhibitors has been demonstrated in preclinical studies, and Phases I and II clinical trials in cancer patients are currently underway.

Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity.[Pubmed:10425100]

J Med Chem. 1999 Jul 29;42(15):2909-19.

The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure Kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesized. Paullones with different substituents in the 2-, 3-, 4-, 9-, and 11-positions were prepared by a Fischer indole reaction starting from 1H-[1]benzazepine-2,5(3H,4H)-diones 5. Selective substitutions at either the lactam or the indole nitrogen atom were accomplished by treating Kenpaullone with alkyl halides in the presence of sodium hydride/THF or potassium hydroxide/acetone, respectively. S-Methylation of the Kenpaullone-derived thiolactam 18 yielded the methylthioimidate 19, which gave the hydroxyamidine 20 upon reaction with hydroxylamine. The new paullones were tested both in a CDK1/cyclin B inhibition assay and in the in vitro antitumor cell line-screening program of the National Cancer Institute (NCI). With respect to the CDK1/cyclin B inhibition, electron-withdrawing substituents in the 9-position as well as a 2,3-dimethoxy substitution on the paullone basic scaffold turned out to be favorable. A 9-trifluoromethyl substituent was found to be equivalent to the 9-bromo substituent of Kenpaullone. Replacement of the 9-bromo substituent of Kenpaullone by a 9-cyano or 9-nitro group produced a substantial increase in enzyme-inhibiting potency. Substitutions in other positions or the replacement of the lactam moiety led to decreased CDK1 inhibition. Noteworthy in vitro antitumor activities (GI(50) values between 1 and 10 microM) were found with the 9-bromo-2,3-dimethoxy-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4t), its 9-trifluoromethyl analogue 4u, the 12-Boc-substituted paullone15, and the methylthioimidate 19, respectively. The 9-nitro-7,12-dihydroindolo[3, 2-d][1]benzazepin-6(5H)-one (4j, named alsterpaullone) showed a high CDK1/cyclin B inhibitory activity (IC(50) = 0.035 microM) and exceeded the in vitro antitumor potency of the other paullones by 1 order of magnitude (log GI(50) mean graph midpoint = -6.4 M).

Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases.[Pubmed:10363974]

Cancer Res. 1999 Jun 1;59(11):2566-9.

Analysis of the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen data using the COMPARE algorithm to detect similarities in the pattern of compound action to flavopiridol, a known inhibitor of cyclin-dependent kinases (CDKs), has suggested several possible novel CDK inhibitors. 9-Bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one, NSC-664704 (Kenpaullone), is reported here to be a potent inhibitor of CDK1/cyclin B (IC50, 0.4 microM). This compound also inhibited CDK2/cyclin A (IC50, 0.68 microM), CDK2/cyclin E (IC50, 7.5 microM), and CDK5/p25 (IC50, 0.85 microM) but had much less effect on other kinases; only c-src (IC50, 15 microM), casein kinase 2 (IC50, 20 microM), erk 1 (IC50, 20 microM), and erk 2 (IC50, 9 microM) were inhibited with IC50s less than 35 microM. Kenpaullone acts by competitive inhibition of ATP binding. Molecular modeling indicates that Kenpaullone can bind in the ATP binding site of CDK2 with residue contacts similar to those observed in the crystal structures of other CDK2-bound inhibitors. Analogues of Kenpaullone, in particular 10-bromopaullone (NSC-672234), also inhibited various protein kinases including CDKs. Cells exposed to Kenpaullone and 10-bromopaullone display delayed cell cycle progression. Kenpaullone represents a novel chemotype for compounds that preferentially inhibit CDKs.

Kenpaullone is a potent inhibitor of CDK1/cyclin B and GSK-3β, with IC50s of 0.4 μM and 23 nM, and also inhibits CDK2/cyclin A, CDK2/cyclin E, and CDK5/p25 with IC50s of 0.68 μM, 7.5 μM, 0.85 μM, respectively.

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