Journal article
Enabling and Disabling Polo-like Kinase 1 Inhibition through Chemical Genetics
ACS chemical biology, Vol.7(6), pp.978-981
06/15/2012
DOI: 10.1021/cb200551p
PMCID: PMC3376236
PMID: 22422077
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, Pik1(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.
Details
- Title: Subtitle
- Enabling and Disabling Polo-like Kinase 1 Inhibition through Chemical Genetics
- Creators
- Mark E. Burkard - Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53706 USAAnna Santamaria - University of BaselPrasad V. Jallepalli - Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA
- Resource Type
- Journal article
- Publication Details
- ACS chemical biology, Vol.7(6), pp.978-981
- DOI
- 10.1021/cb200551p
- PMID
- 22422077
- PMCID
- PMC3376236
- NLM abbreviation
- ACS Chem Biol
- ISSN
- 1554-8929
- eISSN
- 1554-8937
- Publisher
- Amer Chemical Soc
- Number of pages
- 4
- Grant note
- GM094972; GM097245 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA008748 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Flight Attendant Medical Research Institute UL1TR000427 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) 1UL1RR025011 / National Center for Research Resources of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) R01GM097245 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 06/15/2012
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701257202771
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