Structure-Based Design of γ‑Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors

Small-molecule inhibitors of bromodomain
and extra terminal proteins
(BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential
for the treatment of human cancers and other diseases and conditions.
In this paper, we report the design, synthesis, and evaluation of
γ-carboline-containing compounds as a new class of small-molecule
BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins
(BRD2, BRD3, and BRD4) with Ki values
of 3.2–24.7 nM and demonstrates high selectivity over other
non-BET bromodomain-containing proteins. Compound 18 potently
and selectively inhibits cell growth in human acute leukemia cell
lines harboring the rearranged mixed lineage leukemia 1 gene. We have
determined a cocrystal structure of 18 in complex with
BRD4 BD2 at 1.4 Å resolution, which provides a solid structural
basis for the compound’s high binding affinity and for its
further structure-based optimization. Compound 18 represents
a promising lead compound for the development of a new class of therapeutics
for the treatment of human cancer and other conditions.