HIGHLIGHTS
Biomedical
KEVIN BURGESS Texas A&M University, US
Smart evolution of peptides If smart evolution is getting results with less trial-and-error, then a group at the ETH are certainly doing this (Schneider et al, Angew. Chem. Int. Ed., 2019, 58, 1674) (Figure 1). Starting with helical peptides
with known anti-cancer activities, they used an algorithm to generate a small number (~10) of derivative sequences for testing, then used the results of these assays to guide design of the next generation. This process was repeated until the assay
O O N N N pirfenidone
approved for treatment of idiopathic pulmanory fibrosis
HO3S pirfenidone
approved for treatment of idiopathic pulmanory fibrosis
HO3S N+ N+ 1 1 N+ N+ 3 3 N N
X+ -H+
N SO3H SO3H TCEP N HO3S TCEP HO3S PR3 N N R = -(CH2)2CO2H2 2 R = -(CH2)2CO2H
X+ -H+
PR3 N SO3H O O O O N O
N H
cabozantinib O O HN O
N H
cabozantinib O HN O
H N
Begin with peptide having known activity
Figure 1 Smart evolution of peptide cytotoxicity towards cancer cells
output (cytotoxicity in their case) plateaued. Conceptually, this is similar to
‘design of experiments’ protocols. Peptides evolved by this method can then be analysed for parameters such as helical-propensity, hydrophobicity, hydrophobic moment, and
F F O
H N
N O O N sorafenib O HN
N H
O sorafenib CF3
Optimise in silico
test
Repeat until output parameter plateaus
oligomerisation state. This approach is intriguing, although in practice the outcome is underwhelming (statistically significant, but small EC50 improvements, eg from 12 to 4.0µM). I think this is a promising method with an active future ahead of it.
Identification of a new target for chemotherapy of liver cancer A large collaborative team reports on the role of mitogen-activated kinase (MAPK), p38γ, in hepatocellular carcinoma (HCC) (Nature, doi: s41586- 019-1112-8).
HN
N H
This kinase is closely associated with the cyclin dependent kinases (CDKs); it is intimately involved in cell cycle progression, and, in particular, phosphorylation of retinoblastoma proteins. Human liver cancer cells tend to overexpress p38γ, and mice without this protein, or ones treated with a small molecule inhibitor of its activity, are protected against chemically induced tumor formation. That small
Cl CF3 Cl O
molecule inhibitor is a simple compound,
SO3H N N N N+
X 4
E = Cl, Br, I, SCN
X 4
E = Cl, Br, I, SCN N+ N+ R N+
R 5
N R 5 N R
E+ -H+
E+ -H+
N+ R E N+
R 6
E R = alkyl, E = F, Cl, Br, I, NO2, ArCH2 6 R = alkyl, E = F, Cl, Br, I, NO2, ArCH2 N R
pirfenidone, and it is clinically approved in the UK for treatment of pulmonary fibrosis. It must have occurred to the authors that it might be possible to repurpose this pharmaceutical, or analogs of it, for treatment of liver cancer, though one of the side-effects of that drug is to increase certain enzyme levels, which may be problematic. The Nature paper does not mention kinase inhibitors that are FDA-approved for liver cancer, but these include cabozantinib and sorafenib. Cabozantinib and sorafenib are best known as inhibitors of kinases like VEGFR, Raf (they are not very selective) but on digging a little deeper, I found sorafenib at least is known to suppress p38 activity (Scientific Reports, srep44123), hence it seems clear this contributes to the impact it has on HCC.
N R
Nucleophilic and electrophilic attack on cyanine dyes Oligomethine bridges in cyanine dyes have alternating electrophilic and nucleophilic carbons. This arises
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