2 research outputs found
Discovery of PG545: A Highly Potent and Simultaneous Inhibitor of Angiogenesis, Tumor Growth, and Metastasis
Increasing the aglycone lipophilicity of a series of
polysulfated
oligosaccharide glycoside heparan sulfate (HS) mimetics via attachment
of a steroid or long chain alkyl group resulted in compounds with
significantly improved in vitro and ex vivo antiangiogenic activity.
The compounds potently inhibited heparanase and HS-binding angiogenic
growth factors and displayed improved antitumor and antimetastatic
activity in vivo compared with the earlier series. Preliminary pharmacokinetic
analyses also revealed significant increases in half-life following
iv dosing, ultimately supporting less frequent dosing regimens in
preclinical tumor models compared with other HS mimetics. The compounds
also displayed only mild anticoagulant activity, a common side effect
usually associated with HS mimetics. These efforts led to the identification
of 3β-cholestanyl 2,3,4,6-tetra-<i>O</i>-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-<i>O</i>-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-<i>O</i>-sulfo-α-d-glucopyranosyl-(1→4)-2,3,6-tri-<i>O</i>-sulfo-β-d-glucopyranoside, tridecasodium salt (PG545, <b>18</b>) as a clinical candidate. Compound <b>18</b> was recently
evaluated in a phase I clinical trial in cancer patients
Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry
Natural
products are well known for their biological relevance, high degree
of three-dimensionality, and access to areas of largely unexplored
chemical space. To shape our understanding of the interaction between
natural products and protein targets in the postgenomic era, we have
used native mass spectrometry to investigate 62 potential protein
targets for malaria using a natural-product-based fragment library.
We reveal here 96 low-molecular-weight natural products identified
as binding partners of 32 of the putative malarial targets. Seventy-nine
(79) fragments have direct growth inhibition on <i>Plasmodium
falciparum</i> at concentrations that are promising for the development
of fragment hits against these protein targets. This adds a fragment
library to the published HTS active libraries in the public domain