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Bioorg Med Chem. 2008 Aug 1;16(15):7443-9. doi: 10.1016/j.bmc.2008.06.023. Epub 2008 Jun 18.

The discovery of small molecule chemical probes of Bcl-X(L) and Mcl-1.

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Ontario Institute for Cancer Research, MaRS Centre, South Tower, 101 College Street, Toronto, Ont., Canada M5G 1L7.


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.

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