Journal article
Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL
BE Sleebs, WJA Kersten, S Kulasegaram, G Nikolakopoulos, E Hatzis, RM Moss, JP Parisot, H Yang, PE Czabotar, WD Fairlie, EF Lee, JM Adams, L Chen, MF Van Delft, KN Lowes, A Wei, DCS Huang, PM Colman, IP Street, JB Baell Show all
Journal of Medicinal Chemistry | Published : 2013
DOI: 10.1021/jm400556w
Abstract
Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-X L inhibitors originating from a high-throughput screening campaign. Small structural changes to the hit compound increased binding affinity more than 300-fold (to IC50 < 20 nM). This molecular series exhibits drug-like characteristics, low molecular weights (Mw < 450), and unprecedented selectivity for Bcl-XL. Surface plasmon resonance experiments afford strong evidence of binding affinity within the hydrophobic groove of Bcl-XL. Biological experiments using engineered Mcl-1 def..
View full abstractGrants
Funding Acknowledgements
We thank Steve Elmore and Abbvie for providing 1. We also thank our colleagues at the Hall Institute for their work on the Bcl-2 family of proteins that has led to this contribution and for discussions during this work. In particular: Andreas Strasser and Suzanne Cory. This work was supported by fellowships and grants from the Australian Research Council (fellowship to P.E.C.), the National Health and Medical Research Council (NHMRC, fellowships to J.M.A, J.B.B., P.M.C. and D.C.S.H.; development grant 305536 and program grants 257502, 461221 and 1016701), the Leukemia and Lymphoma Society (specialized center of research grant nos. 7015 and 7413), the Cancer Council of Victoria (fellowship to P.M.C.; grant-in-aid 461239) and the Australian Cancer Research Foundation. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme grant no. 361646 and a Victorian State Government OIS grant are gratefully acknowledged.