Structural Insight into Maternal Embryonic Leucine Zipper Kinase (MELK) Conformation and Inhibition toward Structure-Based Drug Design

Canevari, Giulia; Depaolini, Stefania Re; Cucchi, Ulisse; Bertrand, J. A.; Casale, Elena; Perrera, Claudia; Forte, Barbara; Carpinelli, Patrizia; Felder, E.

doi:10.1021/bi4005864

Cited by 28 publications

(16 citation statements)

References 27 publications

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“…Two different crystal morphologies were observed. MELK complexed with Nintedanib, PF-3758309, K-252a and Defactinib yielded rectangular, prism-shaped crystals as described(72); whilst the MELK-BI-847325 complex produced cubic crystals. Crystals were transferred in a cryo-protectant solution (15% PEG 3350, 600 mM NaCl and 100 mM Bis-Tris pH 6.5 and 30% glycerol) prior to flash-cooling in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 83%

The target landscape of clinical kinase drugs

Klaeger

Heinzlmeir

Wilhelm

et al. 2017

Science

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646

706

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Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

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Section: Methodsmentioning

confidence: 83%

The target landscape of clinical kinase drugs

Klaeger

Heinzlmeir

Wilhelm

et al. 2017

Science

Self Cite

646

706

View full text Add to dashboard Cite

show abstract

“…Notably, crystal structures for MELK have recently been published. 25,28 Approximately 1500 compounds constituting an Astex fragment library were screened using ligand observed nuclear magnetic resonance (NMR) spectroscopy and protein thermal shift (T m ). Hits from both biophysical assays were progressed to X-ray crystallography, from which a large number of structurally validated hinge-binding compounds were obtained.…”

Section: Elucidation Of the Role Of Melk In Cancermentioning

confidence: 99%

Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase

Johnson¹,

Berdini²,

Beke

et al. 2014

ACS Med. Chem. Lett.

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Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.

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“…In fact, the structure and signaling pathways of MELK are still being researched. Recent findings about MELK’s structure have uncovered a ubiquitin-associated domain, and an activation segment with a disulfide bond(11, 12). Indeed additional studies are necessary to understand the complex structure and signaling cascade involving MELK.…”

Section: Introductionmentioning

confidence: 99%

Maternal Embryonic Leucine Zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

Ganguly

Hong

Smith

et al. 2014

Molecular Cancer Therapeutics

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Maternal embryonic leucine zipper kinase (MELK) is a member of the snf1/AMPK family of protein Serine/Threonine kinases that has recently gained significant attention in the stem cell and cancer biology field. Recent studies suggest that activation of this kinase is tightly associated with extended survival and accelerated proliferation of cancer stem cells (CSCs) in various organs. Overexpression of MELK has been noted in various cancers, including colon, breast, ovaries, pancreas, prostate, and brain, making the inhibition of MELK an attractive therapeutic strategy for a variety of cancers. In the experimental cancer models, depletion of MELK by RNA interference or small molecule inhibitors induces apoptotic cell death of cancer stem cells derived from glioblastoma and breast cancer, both in vitro and in vivo. Mechanism of action of MELK includes, yet may not be restricted to, direct binding and activation of the oncogenic transcription factors c-JUN and FOXM1 in cancer cells but not in the normal counterparts. Following these pre-clinical studies, the Phase I clinical trial for advanced cancers with OTS167 started in 2013, as the first-in-class MELK inhibitor. This review summarizes the current molecular understanding of MELK and the recent pre-clinical studies about MELK as a cancer therapeutic target.

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Structural Insight into Maternal Embryonic Leucine Zipper Kinase (MELK) Conformation and Inhibition toward Structure-Based Drug Design

Cited by 28 publications

References 27 publications

The target landscape of clinical kinase drugs

The target landscape of clinical kinase drugs

Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase

Maternal Embryonic Leucine Zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

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