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 B. Reed, Tong Ying Shun, Q. Jane Wang, Peter Wipf, John S. Lazo

Research output: Contribution to journalArticle

12 Scopus citations

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

All Science Journal Classification (ASJC) codes

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

Fingerprint Dive into the research topics of 'Discovery of diverse small molecule chemotypes with cell-based PKD1 inhibitory activity'. Together they form a unique fingerprint.

  • Cite this

    Sharlow, E. R., Wilson, G. M., Close, D., Leimgruber, S., Tandon, M., Reed, R. B., Shun, T. Y., Wang, Q. J., Wipf, P., & 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