Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity

Elizabeth R. Sharlow, Gabriela Mustata Wilson, David Close, Stephanie Leimgruber, Manuj Tandon, Robyn Reed, Tong Ying Shun, Q. Jane Wang, Peter Wipf, John S. Lazo

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC 50s for these eleven compounds ranged in potency from 0.4 to 6.1 μM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien-1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target.

Original languageEnglish (US)
Article numbere25134
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - Oct 5 2011

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chemotypes
Adenosine Triphosphate
Molecules
Protein-Serine-Threonine Kinases
Diglycerides
Phorbol Esters
Bioinformatics
Assays
Screening
Phosphotransferases
pathological processes and conditions
protein kinases
Chemical activation
Cells
Throughput
cells
phosphotransferases (kinases)
Pharmacology
furans
prostatic neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sharlow, E. R., Wilson, G. M., Close, D., Leimgruber, S., Tandon, M., Reed, R., ... Lazo, J. S. (2011). Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. PloS one, 6(10), [e25134]. https://doi.org/10.1371/journal.pone.0025134
Sharlow, Elizabeth R. ; Wilson, Gabriela Mustata ; Close, David ; Leimgruber, Stephanie ; Tandon, Manuj ; Reed, Robyn ; Shun, Tong Ying ; Wang, Q. Jane ; Wipf, Peter ; Lazo, John S. / Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. In: PloS one. 2011 ; Vol. 6, No. 10.
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Sharlow, ER, Wilson, GM, Close, D, Leimgruber, S, Tandon, M, Reed, R, Shun, TY, Wang, QJ, Wipf, P & Lazo, JS 2011, 'Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity', PloS one, vol. 6, no. 10, e25134. https://doi.org/10.1371/journal.pone.0025134

Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity. / Sharlow, Elizabeth R.; Wilson, Gabriela Mustata; Close, David; Leimgruber, Stephanie; Tandon, Manuj; Reed, Robyn; Shun, Tong Ying; Wang, Q. Jane; Wipf, Peter; Lazo, John S.

In: PloS one, Vol. 6, No. 10, e25134, 05.10.2011.

Research output: Contribution to journalArticle

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AU - Sharlow, Elizabeth R.

AU - Wilson, Gabriela Mustata

AU - Close, David

AU - Leimgruber, Stephanie

AU - Tandon, Manuj

AU - Reed, Robyn

AU - Shun, Tong Ying

AU - Wang, Q. Jane

AU - Wipf, Peter

AU - Lazo, John S.

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