HIGHLIGHTS
T-cell
Ala-scans to identify a ‘fingerprint’ of key amino acid side chains; (ii) using distance similarity algorithms (Tanimoto parameters) to identify small molecules that present similar pharmacophores with appropriate spacing; (iii) virtual docking protocols to rank candidates; and, (iv) compound purchase and testing. While their method is not ‘clean’ insofar as it generates false positives, and it is also restricted to the chemotypes in virtual libraries of commercially available compounds, which are not ideal for PPIs, it successfully identified several small molecules that bind uPAR and inhibit uPA•uPAR interaction with low micromolar Kd
or Ki values.
Stem cells: glioblastoma and pancreatic cancer It is becoming increasingly clear that cancer stem cells play an important role in metastatic spread and resist- ance to chemotherapy. For instance, a recent paper in Nature from 19 different labs (doi: nature23666) use ‘barcoded’ cancer cells in which biologically inconsequential DNA tags are introduced via lentiviruses.
receptor luciferase PD-1 PD-L1
bioluminescence only if PD-1•PD-L1 blocked
glioblastoma was traced to slow- cycling stem cells, that transform into relatively rapidly recycling progenitor cells, then finally to non-proliferative cells, ie heterogeneity that is not directly genetically encoded. This team was also able to follow the evolution of cancer stem cells resistant to chemotherapy. In the light of studies like the one Highlighted above, chemistry has an important role in oncology research; for instance, compounds that target cancer stem cells could be particularly valuable. One such study is by researchers from Nankai University (Angew. Chem. Int. Ed., doi: anie.201709744).
Thus, the evolution of O
O N O O O ( )10 BE-43547A2 O
N H
NH OH O N O O O ( )10 BE-43547A2 luciferase
Figure 1 Cellular assay for compounds that disrupt the PD-1•PD-L1 interaction; only those that do this will initiate bioluminescence.
PD-1 O O
N H
NH OH
T-like Jurkat
T-like Jurkat
They developed a scalable route T-cell receptor
to BE-43547A2 and noted that the original synthesis reported by Poulsen et al (Nature Chem., 2016, 9, 264) also noted the compound is more toxic to some cancer cell lines under hypoxic conditions that normoxic. Clearly, the Nankai group
appreciate that hypoxia frequently leads to formation of cancer stem cells (CSCs), and postulated BE- 43547A2
might be selectively toxic PD-L1
bioluminescence only if PD-1•PD-L1 blocked
to these. Thus, having enough compound on hand to test, they established BE-43547A2
decreases
the proportion of CSCs in a culture of pancreatic cancer cells, and prevents microsphere formation, a characteristic of metastatic potential. Finally, in the definitive test,
they showed pancreatic cancer cells injected into mice at extremely low levels were far less likely to initiate a tumor if they were pre-treated with BE-43547A2
. Several compounds
that are also selective for pancreatic cancer stem cells are in clinical trials; these were used as controls, and BE-43547A2 throughout.
was the most effective Formulation Forum Launch Event 2018
Wednesday 17 - Thursday 18 January 2018 SCI, London, UK
This is the first in a series of annual 2-day workshop events where participants will learn about formulation science related activities (UK & wider) both currently running and planned.
This event will provide an unparalleled opportunity to meet, build partnerships and network with other members of the community. Current challenges will be raised, identified and discussed in workshops, and paths forward to realise solutions will be proposed.
The Formulation Forum acts as a catalyst for the creation of new projects and investigation of these ideas.
Register today! T: +44 (0)20 7598 1561 E:
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