Kinase inhibitors: the road ahead Ferguson, Fleur M; Gray, Nathanael S
Nature reviews. Drug discovery,
05/2018, Volume:
17, Issue:
5
Journal Article
Peer reviewed
Receptor tyrosine kinase signalling pathways have been successfully targeted to inhibit proliferation and angiogenesis for cancer therapy. However, kinase deregulation has been firmly demonstrated to ...play an essential role in virtually all major disease areas. Kinase inhibitor drug discovery programmes have recently broadened their focus to include an expanded range of kinase targets and therapeutic areas. In this Review, we provide an overview of the novel targets, biological processes and disease areas that kinase-targeting small molecules are being developed against, highlight the associated challenges and assess the strategies and technologies that are enabling efficient generation of highly optimized kinase inhibitors.
Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over ...small molecule inhibitors. We describe dTAG
-1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12
-tagged proteins. dTAG
-1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice.
Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares ...structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BETprotein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BETproteins in human physiology and disease.
Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas. Positron emission tomography (PET) tracers that ...bind to pathological tau are used in diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET-probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01-175 was designed to engage both tau and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4
, to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, with minimal effect on tau from neurons of healthy controls, indicating specificity for disease-relevant forms. QC-01-175 also rescued stress vulnerability in FTD neurons, phenocopying CRISPR-mediated
-knockout. This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.
In this Voices piece, the Cell Chemical Biology editors ask researchers from a range of backgrounds: what are some exciting discoveries in the induced proximity field and the next frontier for ...therapeutic development?
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In this Voices piece, the Cell Chemical Biology editors ask researchers from a range of backgrounds: what are some exciting discoveries in the induced proximity field and the next frontier for therapeutic development?
Binding of the chromatin remodeling complex NoRC to RNA complementary to the rDNA promoter mediates transcriptional repression. TIP5, the largest subunit of NoRC, is involved in recruitment to rDNA ...by interactions with promoter-bound TTF-I, pRNA, and acetylation of H4K16. TIP5 domains that recognize posttranslational modifications on histones are essential for recruitment of NoRC to chromatin, but how these reader modules recognize site-specific histone tails has remained elusive. Here, we report crystal structures of PHD zinc finger and bromodomains from human TIP5 and BAZ2B in free form and bound to H3 and/or H4 histones. PHD finger functions as an independent structural module in recognizing unmodified H3 histone tails, and the bromodomain prefers H3 and H4 acetylation marks followed by a key basic residue, KacXXR. Further low-resolution analyses of PHD-bromodomain modules provide molecular insights into their trans histone tail recognition, required for nucleosome recruitment and transcriptional repression of the NoRC complex.
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•TIP5 and BAZ2B PHD zinc fingers recognize unmodified H3K4•TIP5 and BAZ2B bromodomain recognize H4K16ac and H3K14ac with specific motif KacXXR•Cocrystal structures of individual domains define the basis for histone recognition•SAXS data for BAZ2B suggest independent PTM recognition
Reader domains of chromatin remodeling complexes NoRC/BAZ2B recognize posttranslationally modified histone tails. Tallant et al. reveal the molecular basis for binding specificity of PHD fingers to unmodified H3K4 and bromodomains to a Kac-X-X-R pattern, occurring through structurally independent recognition.
Targeted protein degradation (TPD) refers to the use of small molecules to induce ubiquitin-dependent degradation of proteins. TPD is of interest in drug development, as it can address previously ...inaccessible targets. However, degrader discovery and optimization remains an inefficient process due to a lack of understanding of the relative importance of the key molecular events required to induce target degradation. Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive dataset provides chemical leads for ∼200 kinases and demonstrates that the current practice of starting from the highest potency binder is an ineffective method for discovering active compounds. We develop multitargeted degraders to answer fundamental questions about the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent. This work will not only fuel kinase degrader discovery, but also provides a blueprint for evaluating targeted degradation across entire gene families to accelerate understanding of TPD beyond the kinome.
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•A global map of kinase degradability provides chemical leads for >200 kinases•Open-access chemical proteomics resource (https://proteomics.fischerlab.org)•Large-scale chemical exploration of key variables for targeted protein degradation•Multi-targeted degraders uncover fundamentals of ubiquitin-mediated protein turnover
A synthetic chemistry and chemo-proteomics platform used to annotate the “degradable kinome” provides chemical leads for developing degraders of approximately 200 distinct kinase targets and offers new general design principles for developing future kinase degraders.
Targeted protein degradation using molecular glues is a powerful method for targeting traditionally undruggable proteins. One challenge in molecular glue discovery is the absence of rational ...discovery methods. Here, King et al. leverage covalent library screening with chemoproteomics platforms to rapidly discover a molecular glue targeting NFKB1 via UBE2D recruitment.
Targeted protein degradation using molecular glues is a powerful method for targeting traditionally undruggable proteins. One challenge in molecular glue discovery is the absence of rational discovery methods. Here, King et al. leverage covalent library screening with chemoproteomics platforms to rapidly discover a molecular glue targeting NFKB1 via UBE2D recruitment.
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