Kinase Chemodiversity from the Arctic: The Breitfussins

In this work, we
demonstrate that the indole-oxazole-pyrrole framework
of the breitfussin family of natural products is a promising scaffold
for kinase inhibition. Six new halogenated natural products, breitfussin
C–H (3 – 8) were isolated
and characterized from the Arctic, marine hydrozoan Thuiaria
breitfussi. The structures of two of the new natural products
were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the
survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative
breast cancer cell line MDA-MB-468, while leaving the majority of
the tested cell lines not or significantly less affected. When tested
against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390
nM against the PIM1 and DRAK1 kinases, respectively. The activity
was confirmed to be mediated through ATP competitive binding in the
ATP binding pocket of the kinases. Furthermore, evaluation of potential
off-target and toxicological effects, as well as relevant in vitro
ADME parameters for 3 revealed that the breitfussin scaffold
holds promise for the development of selective kinase inhibitors.