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.
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