The discovery of small molecule chemical probes of Bcl-XL and Mcl-1

Download
  1. Get@NRC: The discovery of small molecule chemical probes of Bcl-XL and Mcl-1 (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1016/j.bmc.2008.06.023
AuthorSearch for: ; Search for: ; Search for: ; Search for: ; Search for:
TypeArticle
Journal titleBioorganic & Medicinal Chemistry
Volume16
Issue15
Pages74437449; # of pages: 7
Subjectapoptosis; Bcl-2 family; chemical biology; combinatorial chemistry; diversity-oriented synthesis; high-throughput synthesis; Mcl-1; natural product-inspired probes; protein-protein interactions; small molecule-protein interactions by NMR
AbstractA tetrahydroaminoquinoline-based library was generated with the goals of finding small molecule modulators of protein-protein interactions. Several library members as well as other related intermediates were tested for their ability to bind to Bcl-XL and Mcl-1 by in silico and 15N NMR studies. The NMR study led to the identification of the tetrahydroaminoquinoline-based nude scaffold, 7 as a weak binder (Kd?=?200?[mu]M for Bcl-XL and Kd?=?300?[mu]M for Mcl-1) to both proteins. Using this scaffold as the starting material, we then synthesized a focused library of only 9 derivatives by applying the principles of a fragment-based approach. All these derivatives were then tested by NMR and this led to the discovery of a novel, small molecule (MIPRALDEN, 17) as a binder to Mcl-1 and Bcl-XL (KD?=?25 and 70?[mu]M). This finding is novel because to our knowledge there are not many small molecules known in the literature that bind to Mcl-1.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada; NRC Steacie Institute for Molecular Sciences
Peer reviewedNo
NPARC number12338876
Export citationExport as RIS
Report a correctionReport a correction
Record identifierf1e17f7e-473f-4663-9a5b-8bd20e7ba751
Record created2009-09-11
Record modified2016-05-09
Bookmark and share
  • Share this page with Facebook (Opens in a new window)
  • Share this page with Twitter (Opens in a new window)
  • Share this page with Google+ (Opens in a new window)
  • Share this page with Delicious (Opens in a new window)