The discovery of small molecule chemical probes of Bcl-X(L) and Mcl-1.
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.
Prakesch
Michael
M
Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Toronto, Ont., Canada M5G 1L7.
Denisov
Alexey Yu
AY
Naim
Marwen
M
Gehring
Kalle
K
Arya
Prabhat
P
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*
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D051020:bcl-X Protein