Pharmacokinetic characterization of a natural product–inspired novel MEK1 inhibitor E6201 in preclinical species

Kumar, Vipul; Schuck, Edgar; Pelletier, Robert; Farah, Nadia; Condon, Krista; Ye, Meng; Rowbottom, Christopher; King, Belinda M.; Zhang, Zhiyi; Saxton, Philip L.; Wong, Y. Nancy

doi:10.1007/s00280-011-1687-8

Cited by 11 publications

(9 citation statements)

References 13 publications

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“…Hypothemycin (Tanaka et al, 1999) and related compounds (Barluenga et al, 2010) have antitumor activity in mouse xenograft models, and one variant has entered clinical trials (Kumar et al, 2011). All hypothemycin-sensitive kinases have a common cysteine immediately preceding the catalytic DXG motif (where X is usually Phe or Leu) (Schirmer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

Nishino

Choy

Gushwa

et al. 2013

eLife

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Protein kinases are potentially attractive therapeutic targets for neglected parasitic diseases, including African trypanosomiasis caused by the protozoan, Trypanosoma brucei. How to prioritize T. brucei kinases and quantify their intracellular engagement by small-molecule inhibitors remain unsolved problems. Here, we combine chemoproteomics and RNA interference to interrogate trypanosome kinases bearing a Cys-Asp-Xaa-Gly motif (CDXG kinases). We discovered that hypothemycin, a fungal polyketide previously shown to covalently inactivate a subset of human CDXG kinases, kills T. brucei in culture and in infected mice. Quantitative chemoproteomic analysis with a hypothemycin-based probe revealed the relative sensitivity of endogenous CDXG kinases, including TbGSK3short and a previously uncharacterized kinase, TbCLK1. RNAi-mediated knockdown demonstrated that both kinases are essential, but only TbCLK1 is fully engaged by cytotoxic concentrations of hypothemycin in intact cells. Our study identifies TbCLK1 as a therapeutic target for African trypanosomiasis and establishes a new chemoproteomic tool for interrogating CDXG kinases in their native context.DOI: http://dx.doi.org/10.7554/eLife.00712.001

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Section: Introductionmentioning

confidence: 99%

“…We have changed the text to clarify our rationale for pursuing trypanosome targets. As mentioned in the main text, hypothemycin and derivatives have been previously used in mice (Tanaka et al, 1999; Barluenga et al, 2010) and in humans (Kumar et al, 2011). We are unaware of any hemolytic activity of hypothemycin or its derivatives.…”

mentioning

confidence: 99%

Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

Nishino

Choy

Gushwa

et al. 2013

eLife

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“…Derivatization of hypothemycin led to several inhibitors with good potency for TAK1, FLT, and MEK, as well as to the drug candidate E6201. [29] Recently,h ypothemycin has also been shown to be effective at killing the protozoan Trypanosoma brucei by targeting kinases with aD FG (À1) cysteine in this pathogen. [30] Several other natural products harbouring Michael acceptors have been reported to inhibit kinases,f or example,I KKb is inhibited by prostaglandin A1, [31] pentacyclic triterpenoid celastrol, [32] 17-acetoxyjolkinolide B [33] and Ainsliadimer A.…”

Section: Cysteine-targeting Electrophilesmentioning

confidence: 99%

The Cysteinome of Protein Kinases as a Target in Drug Development

et al. 2018

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Drugs that function through covalent bond formation represent a considerable fraction of our repository of effective medicines but safety concerns and the complexity of developing covalent inhibitors has rendered covalent targeting a less attractive strategy for rational drug design. The recent approval of four covalent kinase inhibitors and the development of highly potent covalent kinase probes with exceptional selectivity has raised significant interest in industry and academic research and validated the concept of covalent kinase targeting for clinical applications. The abundance of cysteines at diverse positions in and around the kinase active site suggests that a large fraction of kinases can be targeted by covalent inhibitors. Herein, we review recent developments of this rapidly growing area in kinase drug development and highlight the unique opportunities and challenges of this strategy.

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“…The wholly synthetic drug candidate E6201, described as a dual MEK1 and FLT3 inhibitor, is in early clinical trials for advanced hematologic malignancies with documented FLT3 mutation [31]. The pharmacokinetics of E6201 in preclinical species and in humans is characterized by moderate to high distribution but rapid clearance [32]. This PK profile might be regarded as appropriate for a drug exhibiting covalent pharmacology, since high distribution allows the compound to get to its target, but rapid clearance means that unbound, potentially reactive molecules are removed from circulation.…”

Section: Improving Drug Properties For Known Scaffoldsmentioning

confidence: 99%

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

Hallenbeck¹,

Turner²,

Renslo³

et al. 2016

CTMC

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The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an ‘allele specific’ manner. For the medicinal chemist, the structure-guided design of cysteine-reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteine-modifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues.

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Pharmacokinetic characterization of a natural product–inspired novel MEK1 inhibitor E6201 in preclinical species

Cited by 11 publications

References 13 publications

Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

The Cysteinome of Protein Kinases as a Target in Drug Development

Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery

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