posted on 2021-02-01, 20:35authored byWilliam Nguyen, Erinna F. Lee, Marco Evangelista, Mihwa Lee, Tiffany J. Harris, Peter M. Colman, Nicholas A. Smith, Luke B. Williams, Kate E. Jarman, Kym N. Lowes, Cécile Haeberli, Jennifer Keiser, Brian J. Smith, W. Douglas Fairlie, Brad E. Sleebs
Limited
therapeutic options are available for the treatment of
human schistosomiasis caused by the parasitic Schistosoma flatworm.
The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway
in schistosomes was recently characterized and shown to share similarities
with the intrinsic apoptosis pathway in humans. Here, we exploit structural
differences in the human and schistosome BCL-2 (sBCL-2) pro-survival
proteins toward a novel treatment strategy for schistosomiasis. The
benzothiazole hydrazone scaffold previously employed to target human
BCL-XL was repurposed as a starting point to target sBCL-2. We utilized
X-ray structural data to inform optimization and then applied a scaffold-hop
strategy to identify the 5-carboxamide thiazole hydrazone scaffold
(43) with potent sBCL-2 activity (IC50 30
nM). Human BCL-XL potency (IC50 13 nM) was inadvertently
preserved during the optimization process. The lead analogues from
this study exhibit on-target activity in model fibroblast cell lines
dependent on either sBCL-2 or human BCL-XL for survival. Further optimization
of the thiazole hydrazone class is required to exhibit activity in
schistosomes and enhance the potential of this strategy for treating
schistosomiasis.