The discovery of small molecule chemical probes of Bcl-XL 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-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 μM for Bcl-XL and Kd = 300 μM 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 μM). 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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