Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 2, Pages 592-608Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01369
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Funding
- NIH [GM58888, CA107331, GM070855, CA154274]
- National Institute of General Medical Sciences in the National Institutes of Health [P41 GM103403]
- U.S. Department of Energy (DOE) [DE-AC02-06CH11357]
- U.S. Department of Energy, Office of Science, and Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Institutes of Health [S10 RR10441, S10 RR15741, S10 RR16812, S10 RR23447]
- National Science Foundation [DBI 1005795]
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The drug pentamidine inhibits calcium-dependent complex formation with p53 ((Ca)S100Bp53) in malignant melanoma (MM) and restores p53 tumor suppressor activity in vivo. However, off-target effects associated with this drug were problematic in MM patients. Structure-activity relationship (SAR) studies were therefore completed here with 23 pentamidine analogues, and X-ray structures of (Ca)S100Binhibitor complexes revealed that the C-terminus of S100B adopts two different conformations, with location of Phe87 and Phe88 being the distinguishing feature and termed the FF-gate. For symmetric pentamidine analogues ((Ca)S100B5a, (Ca)S100B6b) a channel between sites 1 and 2 on S100B was occluded by residue Phe88, but for an asymmetric pentamidine analogue ((Ca)S100B17), this same channel was open. The (Ca)S100B17 structure illustrates, for the first time, a pentamidine analog capable of binding the open form of the FF-gate and provides a means to block all three hot spots on (Ca)S100B, which will impact next generation (Ca)S100Bp53 inhibitor design.
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