title: The discovery of small molecule chemical probes of Bcl-X(L) and Mcl-1.
abstract: A 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-X(L) and Mcl-1 by in silico and (15)N NMR studies. The NMR study led to the identification of the tetrahydroaminoquinoline-based nude scaffold, 7 as a weak binder (K(d)=200 microM for Bcl-X(L) and K(d)=300 microM 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-X(L) (K(D)=25 and 70 microM). This finding is novel because to our knowledge there are not many small molecules known in the literature that bind to Mcl-1.
authors.affiliation: Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Toronto, Ont., Canada M5G 1L7.
authors.forename: Michael
authors.initials: M
authors.lastname: Prakesch
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Denisov
authors.forename: Marwen
authors.initials: M
authors.lastname: Naim
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.forename: Prabhat
authors.initials: P
authors.lastname: Arya
mesh_terms: D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000737:chemistry*
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D051020:bcl-X Protein