F O F F HN F F O entrectinib HN
H N
N
panTrk kinase inhibitor HN
O H2N
H N
O NH2 O H2N
H N
O NH2 O NH2 O
N H O
H2N
H N
O
N H O
O NH2
H N
O O
N H O
H N
O
N H O
OH + H2N
OH +HN NH2H2N NH
O NH2 O entrectinib O
panTrk kinase inhibitor O
N H O
H2N
H N
O
N H O
2
H N
O
N H O
H N
O
proteases localized in prostate cancer
N H O
HN NH2 NH
2 O
proteases localized in prostate cancer
HN
HN NH2 NH
O F 1
H N
HN NH2 NH
O O
H N
O NH2 NH2
Figure 2 Fluorogenic probe for prostate cancer activated by proteases
N O N F N 1 HN O N N N
H N
N N N HN O N N F O 11CH3
rather than methyls in the spacer fragment shifts the fluorescence of the probe to the red, making it more visible in tissue. This change also decreases the rate of background hydrolysis at the cyanine ‘meso’ position.
Agonists of TrkB, or not TrkB Docking of brain-derived neurotrophic factor (BDNF) with the cell surface tropomyosin kinase receptor B (TrkB) is a fundamental process involved in nerve cell development, synapse formation and plasticity. There have been many efforts to develop TrkB agonists that might be used as probes or therapeutic leads for neurodegenerative diseases, and consequently several compounds have been presented as TrkB agonists. However, many of these compounds are hydrophobic and unlikely to be selective binders, and even less likely to induce selective phosphorylation of the Trk receptors. Sames’ group at Columbia,
OH O NH2
in collaboration with the Neurotechnology Center there, and researchers from The Broad Institute have ‘cleaned house’ in this area (Sci. Signaling, doi: eaal1670.) They showed that most of these
OH
compounds do not act as agonists at TrkB in vitro, although they concede some may influence pathways involving TrkB in vivo.
drug HO3S fluor N HO3S( )4 SO3H O fluor N ( )4 SO3H O
O O EtN
safety-catch SO3H EtN drug
O O EtN
EtN N+ ( )4 SO3H
safety-catch ( )4
N+ SO3H
(i) 1O2 (small amounts generated when Cy5
derivative is illuminated) (ii) thermal decomposition
SO3H
(i) 1O2 (small amounts generated when Cy5
derivative is illuminated) (ii) thermal decomposition
HO3S
drug OH
N HO3S( )4 SO3H O N ( )4 SO3H O O O OH N+ ( )4 SO3H O O OH
drug OH
Et N O N Et Et N O ( )4
N+ Et
N SO3H SO3H SO3H
11CH3
HIGHLIGHTS
3
3
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