Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells

Michael F.T. Koehler, Philippe Bergeron, Elizabeth M. Blackwood, Krista Bowman, Kevin R. Clark, Ron Firestein, James R. Kiefer, Klaus Maskos, Mark L. McCleland, Linda Orren, Laurent Salphati, Steve Schmidt, Elisabeth V. Schneider, Jiansheng Wu, Maureen H. Beresini

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

Abstract

Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-πinteraction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.

Original languageEnglish
Pages (from-to)223-228
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
Issue number3
DOIs
Publication statusPublished - Mar 2016
Externally publishedYes

Keywords

  • CDK8
  • cyclin C
  • kinase inhibitor

Cite this

Koehler, Michael F.T. ; Bergeron, Philippe ; Blackwood, Elizabeth M. ; Bowman, Krista ; Clark, Kevin R. ; Firestein, Ron ; Kiefer, James R. ; Maskos, Klaus ; McCleland, Mark L. ; Orren, Linda ; Salphati, Laurent ; Schmidt, Steve ; Schneider, Elisabeth V. ; Wu, Jiansheng ; Beresini, Maureen H. / Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells. In: ACS Medicinal Chemistry Letters. 2016 ; Vol. 7, No. 3. pp. 223-228.
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abstract = "Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-πinteraction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2{\%} and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.",
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Koehler, MFT, Bergeron, P, Blackwood, EM, Bowman, K, Clark, KR, Firestein, R, Kiefer, JR, Maskos, K, McCleland, ML, Orren, L, Salphati, L, Schmidt, S, Schneider, EV, Wu, J & Beresini, MH 2016, 'Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells', ACS Medicinal Chemistry Letters, vol. 7, no. 3, pp. 223-228. https://doi.org/10.1021/acsmedchemlett.5b00278

Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells. / Koehler, Michael F.T.; Bergeron, Philippe; Blackwood, Elizabeth M.; Bowman, Krista; Clark, Kevin R.; Firestein, Ron; Kiefer, James R.; Maskos, Klaus; McCleland, Mark L.; Orren, Linda; Salphati, Laurent; Schmidt, Steve; Schneider, Elisabeth V.; Wu, Jiansheng; Beresini, Maureen H.

In: ACS Medicinal Chemistry Letters, Vol. 7, No. 3, 03.2016, p. 223-228.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Blackwood, Elizabeth M.

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AU - Clark, Kevin R.

AU - Firestein, Ron

AU - Kiefer, James R.

AU - Maskos, Klaus

AU - McCleland, Mark L.

AU - Orren, Linda

AU - Salphati, Laurent

AU - Schmidt, Steve

AU - Schneider, Elisabeth V.

AU - Wu, Jiansheng

AU - Beresini, Maureen H.

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