The discovery of small molecule chemical probes of Bcl-X sub(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 sub(L) and Mcl-1 by in silico and super(15)N NMR studies. The NMR study led to the identification of the tetrahydroaminoquinoline-based nude scaffold, 7 as a weak binder (K sub(d) = 200 mu M for Bcl-X sub(L) and K sub(d) = 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-X sub(L) (K sub(D) = 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.