Enabling and disabling polo-like kinase 1 inhibition through chemical genetics Journal Article


Authors: Burkard, M. E.; Santamaria, A.; Jallepalli, P. V.
Article Title: Enabling and disabling polo-like kinase 1 inhibition through chemical genetics
Abstract: Polo-like kinase 1 (Plk1) is a core regulator of cell division and an emerging target for cancer therapy. Pharmacologic inhibitors of Plk1 exist but affect other kinases, complicating their in vivo validation. To address this, we examined effects of two structurally unrelated Plk1 inhibitors (BI-2536 and TAL) against isogenic human cell lines that solely express wildtype (wt) or analogue-sensitive (as) Plk1 alleles. Unexpectedly, Plk1 as cells displayed profound biochemical and functional resistance to both inhibitors. Cells that co-express Plk1 wt and Plk1 as exhibit loss-of-function phenotypes only when both kinase alleles are inhibited. Resistance to BI-2536 is linked to an intragenic suppressor mutation (C67V) that restores an otherwise invariant valine to the kinase active site. Structural modeling demonstrates that this mutation not only enables Plk1 as to function in vivo but also occludes BI-2536 from the ATP-binding pocket. Our results reveal the molecular basis of Plk inhibitor selectivity and a potential mechanism for tumor cell resistance. © 2012 American Chemical Society.
Keywords: controlled study; protein expression; unclassified drug; gene mutation; human cell; mutation; proto-oncogene proteins; binding affinity; protein function; phenotype; cell cycle proteins; allele; cell cycle; cell division; enzyme inhibition; amino acid substitution; cell line; in vivo study; drug resistance; drug selectivity; wild type; protein kinase inhibitors; drug mechanism; polo like kinase 1; protein-serine-threonine kinases; gene repression; cell cycle arrest; chemical genetics; crystal structure; aniline compounds; adenosine triphosphate; enzyme structure; loss of function mutation; protein kinase; cysteine; valine; nocodazole; enzyme active site; protein serine threonine kinase inhibitor; 4 (8 cyclopentyl 7 ethyl 5,6,7,8 tetrahydro 5 methyl 6 oxo 2 pteridinylamino) 3 methoxy n (1 methyl 4 piperidinyl)benzamide; pteridines; polo like kinase inhibitor; polo like kinase 1 inhibitor; zk thiazolidinone; thiazolidines
Journal Title: ACS Chemical Biology
Volume: 7
Issue: 6
ISSN: 1554-8929
Publisher: American Chemical Society  
Date Published: 2012-06-15
Start Page: 978
End Page: 981
Language: English
DOI: 10.1021/cb200551p
PROVIDER: scopus
PMCID: PMC3376236
PUBMED: 22422077
DOI/URL:
Notes: --- - "Export Date: 2 July 2012" - "CODEN: ACBCC" - "Source: Scopus"
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