Interrogating the Druggability of the 2-Oxoglutarate-Dependent Dioxygenase Target Class by Chemical Proteomics.
ACS Chemical Biology 11(7):2002 (2016)
The 2-oxoglutarate-dependent dioxygenase target class comprises around 60 enzymes including several subfamilies with relevance to human disease, such as the prolyl hydroxylases and the Jumonji-type lysine demethylases. Current drug discovery approaches are largely based on small molecule inhibit...
Functional interdependence of BRD4 and DOT1L in MLL leukemia.
Nature Structural & Molecular Biology 23(7):673 (2016)
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative...
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.
Journal of medicinal and pharmaceutical chemistry 59(4):1357 (2016)
Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and...
Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives.
Journal of medicinal and pharmaceutical chemistry 59(4):1370 (2016)
Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A numbe...
Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.
Journal of medicinal and pharmaceutical chemistry 59(4):1425 (2016)
Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and an...
Discovery of Novel Small Molecules that Activate Satellite Cell Proliferation and Enhance Repair of Damaged Muscle.
ACS Chemical Biology 11(2):518 (2016)
Skeletal muscle progenitor stem cells (referred to as satellite cells) represent the primary pool of stem cells in adult skeletal muscle responsible for the generation of new skeletal muscle in response to injury. Satellite cells derived from aged muscle display a significant reduction in regene...
Screening Pools of Compounds against Multiple Endogenously Expressed Targets in a Chemoproteomics Binding Assay.
Journal of Laboratory Automation 21(1):133 (2016)
Chemoproteomics-based competition-binding assays allow the screening of compounds against endogenous proteins in cell or tissue extracts, but these assays are hampered by low throughput and high cost. Using compound pools rather than single compounds in a screening campaign holds the promise of ...
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
PLoS ONE 11(3):e0149996 (2016)
In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds' mechanisms of action--i.e., the specific molecular targets by which they kill the parasite--would further facilitate the drug development...
Thermal proteome profiling monitors ligand interactions with cellular membrane proteins.
Nature Methods 12(12):1129 (2015)
We extended thermal proteome profiling to detect transmembrane protein-small molecule interactions in cultured human cells. When we assessed the effects of detergents on ATP-binding profiles, we observed shifts in denaturation temperature for ATP-binding transmembrane proteins. We also observed ...
New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
Nature Chemical Biology 11(11):878 (2015)
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bi...
Thermal proteome profiling for unbiased identification of direct and indirect drug targets using multiplexed quantitative mass spectrometry.
Nature Protocols 10(10):1567 (2015)
The direct detection of drug-protein interactions in living cells is a major challenge in drug discovery research. Recently, we introduced an approach termed thermal proteome profiling (TPP), which enables the monitoring of changes in protein thermal stability across the proteome using quantitat...
Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.
Nature Chemical Biology 11(3):189 (2015)
PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of huma...
Kruidenier et al. reply.
Nature 514(7520):E2 (2014)
Chemoproteomics reveals time-dependent binding of histone deacetylase inhibitors to endogenous repressor complexes.
ACS Chemical Biology 9(8):1736 (2014)
Class I histone deacetylases (HDACs) are attractive drug targets in oncology and inflammation. However, the development of selective inhibitors is complicated by the characteristic that the localization, activity, and selectivity of class I HDACs are regulated by association in megadalton repres...
Drug selectivity: Running in the family.
Nature Chemical Biology 10(8):608 (2014)
The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains.
ACS Chemical Biology 9(2):495 (2014)
A commonly used small-molecule probe in cell-signaling research is the phosphoinositide 3-kinase inhibitor LY294002. Quantitative chemoproteomic profiling shows that LY294002 and LY303511, a close analogue devoid of PI3K activity, inhibit the BET bromodomain proteins BRD2, BRD3, and BRD4 that co...
Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor.
Journal of medicinal and pharmaceutical chemistry 56(7):3012 (2013)
Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2...
Affinity profiling of the cellular kinome for the nucleotide cofactors ATP, ADP, and GTP.
ACS Chemical Biology 8(3):599 (2013)
Most kinase inhibitor drugs target the binding site of the nucleotide cosubstrate ATP. The high intracellular concentration of ATP can strongly affect inhibitor potency and selectivity depending on the affinity of the target kinase for ATP. Here we used a defined chemoproteomics system based on ...
Chemical proteomic analysis reveals the drugability of the kinome of Trypanosoma brucei.
ACS Chemical Biology 7(11):1858 (2012)
The protozoan parasite Trypanosoma brucei is the causative agent of African sleeping sickness, and there is an urgent unmet need for improved treatments. Parasite protein kinases are attractive drug targets, provided that the host and parasite kinomes are sufficiently divergent to allow specific...
A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response.
Nature 488(7411):404 (2012)
The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Conside...