MELK is not necessary for the proliferation of basal-like breast cancer cells

Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK k...

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Bibliographic Details
Published in:eLife Vol. 6; no. 9, 2017
Main Authors: Huang, Hai-Tsang, Seo, Hyuk-Soo, Zhang, Tinghu, Wang, Yubao, Jiang, Baishan, Li, Qing, Buckley, Dennis L, Nabet, Behnam, Roberts, Justin M, Paulk, Joshiawa, Dastjerdi, Shiva, Winter, Georg E, McLauchlan, Hilary, Moran, Jennifer, Bradner, James E, Eck, Michael J, Dhe-Paganon, Sirano, Zhao, Jean J, Gray, Nathanael S
Format: Journal Article
Language:English
Published: England eLife Sciences Publications Ltd 19.09.2017
eLife Sciences Publications, Ltd
Subjects:
basal-like breast cancer
Breast cancer
Breast Neoplasms - pathology
Cancer Biology
Cell Biology
Cell culture
Cell cycle
Cell Line, Tumor
Cell Proliferation
Clonal deletion
CRISPR
Drug discovery
Embryogenesis
Enzyme inhibitors
Gene Knockdown Techniques
Gene Knockout Techniques
HTH-01-091
Humans
Hypothesis testing
Kinases
Leucine zipper proteins
Life sciences
Medical research
MELK
OTSSP167
Protein-Serine-Threonine Kinases - analysis
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - genetics
Proteins
RNA-mediated interference
target validation
Tumors
basal-like breast cancer
MELK
cell biology
HTH-01-091
target validation
OTSSP167
cancer biology
human
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary:Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, a novel chemical-induced protein degradation strategy, RNA interference and CRISPR interference to validate MELK as a therapeutic target in basal-like breast cancers (BBC). In common culture conditions, we found that small molecule inhibition, genetic deletion, or acute depletion of MELK did not significantly affect cellular growth. This discrepancy to previous findings illuminated selectivity issues of the widely used MELK inhibitor OTSSP167, and potential off-target effects of MELK-targeting short hairpins. The different genetic and chemical tools developed here allow for the identification and validation of any causal roles MELK may play in cancer biology, which will be required to guide future MELK drug discovery efforts. Furthermore, our study provides a general framework for preclinical target validation.
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ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.26693