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Title: Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.
Austin Authors: Nguyen, William;Lee, Erinna F;Evangelista, Marco;Lee, Mihwa;Harris, Tiffany J ;Colman, Peter M;Smith, Nicholas A;Williams, Luke B;Jarman, Kate E;Lowes, Kym N;Haeberli, Cécile;Keiser, Jennifer;Smith, Brian J;Fairlie, Walter Douglas ;Sleebs, Brad E
Affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia
Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia
La Trobe Institute for Molecular Science, La Trobe University, Melbourne 3086, Australia
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Melbourne 3086, Australia
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel 4002, Switzerland
University of Basel, Basel 4001, Switzerland
Department of Veterinary Biosciences, The University of Melbourne, Parkville 3010, Australia
Issue Date: 14-May-2021
Date: 2021-02-01
Publication information: ACS Infectious Diseases 2021; 7(5): 1143-1163
Abstract: 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.
DOI: 10.1021/acsinfecdis.0c00700
ORCID: 0000-0003-0498-1910
Journal: ACS Infectious Diseases
PubMed URL: 33523649
Type: Journal Article
Subjects: BCL-2
Appears in Collections:Journal articles

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