HO3S HIGHLIGHTS N SO3H 3
site for connection to folate Ar
N+
red-shifted fluorescence to over 800 nm ( )4
( )4 SO3H entrectinib panTrk kinase inhibitor
F CO2H F HN O HN O F 1
N
H N
N N N HN O N N
(A) varied
fixed
known preference CONH2 protease
N H
O O CONH2 protease
N H
O O CONH2 protease
N H
X x X mixtures tested seperately throughout
positional scanning defines preferred sequence here
(B) fluor 1 A B C D
covalent binding group
fluor 2 A B C D O O H2N O O
fluorescent output only in wells that contain a compatible N-terminal sequence
H2N O O CONH2 H2N O O CONH2 CONH2
Figure 1 (A) Mixtures of peptides in which one position is systematically varied are prepared and tested to reveal the preferred consensus sequence for each enzyme. (B) The consensus sequence for each of the four serine proteases are attached to a N-terminal conspicuous fluor and a C-terminal suicide
fluor 3
A
B
C
D
fluor 4
A
B
C
D
for the featured serine proteases are transformed into affinity labels that fluorescently track these enzymes without becoming dissociated. Thus, four different enzymes could be tracked using four systems bearing complementary fluors.
TrkB/C selective PET ligand A huge team from 14 research institutions have developed a PET (positron emission tomography) probe for TrkB/C and used it to visualise these receptors in vivo and clinically in the human brain (J. Med. Chem., doi:
acs.jmedchem.7b00396). Targeting the kinase domain
enables differentiation full-length receptors from truncated isoforms that lack this site. The probe is permeable to the blood-brain-barrier.
It is based on a substance called entrectinib that is in phase II clinical trials for various but very specific forms of cancer. Overall, this research is important
because overexpression of Trk receptors are associated with various forms of metastatic cancer (ie neuroblastoma, glioblastoma) and lack of function may be involved in various neurological diseases.
Probes for in vivo imaging, and delivery A classical approach to optical probes for tumor imaging is to couple a fluor to a substrate for enzymes that accumulate around tumors, and design the conjugate so that a fluor becomes more brilliant after the enzymes have acted on the probe. For instance, 2 was designed
with a peptide substrate for hepsin and matriptase, proteases that are found in prostate cancer (Yogo et al, Bioconjugate Chem., doi: acs. bioconjchem.7b00233). Hydrolysis of the C-terminal amide bond liberates a rhodamine, that was hitherto ‘caged’ in the complete probe (Figure 2).
In the latest of several papers, Schnermann at the National Cancer Institute in the US has elaborated on his strategy for liberation of cytotoxic cargoes by self-induced oxidative decomposition of cyanine dyes (ACS Central Science, 2017, 3, 329). Figure 2 shows one of the
decomposition pathways that may be operative. The advantage of this strategy is that the tumour- accumulation of drug-antibody conjugates like 3 is revealed by near-IR optical imaging, then stronger prolonger illumination liberates the cytotoxic drug in its more lethal, unconjugated form. In this particular paper, this group shows that having two ethyl groups
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