Fragment merging for Mcl-1

One of the most heroic examples of fragment-based drug discovery is navitoclax (ABT-263), which blocks the anti-apoptotic proteins Bcl-xL and Bcl-2 from binding to their partner proteins. This Abbott (AbbVie?) compound is in Phase 1 and 2 clinical trials for a variety of cancers. Abbott has also reported inhibitors of Bcl-2 that don’t inhibit Bcl-xL. However, many cancer cells are unfazed by inhibitors of Bcl-2 and Bcl-xL because they can instead rely on another protein, Mcl-1. Thus, ABT-263 can be overcome when cancer cells overexpress Mcl-1. Previously, Mcl-1 had been considered by many to be a “Teflon target.” Happily, it has now been successfully tackled with fragments.

The work, published recently in J. Med. Chem., was led by Stephen Fesik, now at Vanderbilt University. Fesik was one of the inventors of the SAR by NMR technique that led to navitoclax, and in this case the team used a similar approach, screening a fairly large fragment library (> 13,800 compounds) in pools of 12 using ¹H-¹⁵N HMQC NMR. This produced 132 hits, of which two chemical classes were pursued.

One chemical class, exemplified by compound 2, consisted of 6,5-fused heterocyclic carboxylic acids, while another class, exemplified by compound 17, consisted of hydrophobic aromatic groups separated by a linker from a (usually) anionic substituent. NOE-guided fragment docking indicated that these compounds bind in similar but non-overlapping regions of Mcl-1, suggesting a fragment-merging approach.

Indeed, merging the compounds led to nanomolar binders such as compounds 60 and 53, which were also completely selective against Bcl-xL and more than 15-fold selective against Bcl-2. Crystal structures of these molecules bound to Mcl-1 confirmed the binding hypothesis. A number of additional analogs were synthesized; pleasingly, the SAR of the isolated fragments generally translated to the merged compounds.

This is a beautiful example of FBLD in academia. Of course, there is still a long way to go: there is a large and disconcerting disconnect between biochemical and cell-based potency for many reported Bcl-family inhibitors, and the lack of cell data here suggests that the same may hold true for Mcl-1. Still, it is nice to see that a venerable technique can succeed against this challenging protein.