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

Nishino, Mari; Choy, Jonathan W; Gushwa, Nathan N; Oses-Prieto, Juan A.; Koupparis, Kyriacos; Burlingame, Alma L.; Renslo, Adam R.; McKerrow, James H.; Taunton, Jack

doi:10.7554/elife.00712

Cited by 44 publications

(69 citation statements)

References 50 publications

(67 reference statements)

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“…We elected to characterize advanced kinase inhibitors in this study, but chemoproteomics can also facilitate the discovery of kinases that are targeted by covalent inhibitors in phenotypic screens 41 . As a greater number of covalent kinase inhibitors are examined using chemoproteomics, it will be interesting to determine whether a finite set of specific off-targets is identified.…”

Section: Discussionmentioning

confidence: 99%

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors

et al. 2014

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Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in kinase active-sites have emerged as valuable probes and approved drugs. Many protein classes, however, possess functional cysteines and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative mass spectrometry to globally map the targets, both specific and non-specific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent non-kinase proteins that, interestingly, possess conserved, active-site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental roadmap to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors

et al. 2014

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“…102 RALs have been used as chemical biology probes, where an alkyne tagged hypothemycin 266 was used to identify the kinase Trypanosoma brucei CDC2-like kinase ( Tb CLK1) as a target for treating Human African trypanosomiasis (Figure 30). 103 Synthetic strategies to access RALs have been reviewed, 101a, 101b and SAR studies have observed that nearly all modifications resulted in lower activity compared to the natural product LL-Z1640-2 ( 267 ). 102 Addition of a methyl group to the α or β position of the enone ( 268 and 269 ) completely abolished activity for the inhibition of tumor necrosis factor phospholipase A2-activating protein (TNFα-PLAP), while an α-fluoro substituent ( 270 ) resulted in a small 3-fold decrease in activity relative to the parent natural product 267 (Figure 30).…”

Section: αβ-Unsaturated Ketones (Enones)mentioning

confidence: 99%

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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“…They used the X-ray structure of hypothemycin bound to ERK2 (Fig. 2C ) to design a propargyl analog of hypothemycin for labeling and pull-down applications [64]. Application of this probe to T. brucei lysates, followed by ‘click’ conjugation of a fluorescent dye, allowed putative protein targets to be visualized by SDS-PAGE.…”

Section: Identifying New 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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Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei

Cited by 44 publications

References 50 publications

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors

A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

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

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