Multi-Water Bridges Enable Design of BET BD1-Selective Inhibitors for Pancreatic Cancer Therapy

Rational design of bromodomain (BD)-selective inhibitors
could
mitigate on-target toxicities associated with pan-BET inhibition but
is challenging despite the availability of high-resolution structures.
By simultaneously forming water bridges with BD1-specific residues
in both the BC ring and the ZA channel, we identified a potent and
orally bioavailable BET BD1-selective inhibitor DDO-8958, which exhibited a KD of 5.6 nM for
BRD4 BD1 and a 214-fold selectivity for BRD4 BD1 over BD2. The cocrystal
structure demonstrated a unique multi-water bridge mechanism involving
BD1-specific residues K91- and D145-driven BD1 selectivity. DDO-8958 extensively influenced the oncogene expression and
metabolic pathway, including oxidative phosphorylation in MIA PaCa-2. In vivo, DDO-8958 inhibited tumor growth and
markedly augmented the therapeutic efficacy of the glycolysis inhibitor
2-DG. These findings illuminate that multi-water bridges enable design
of BD1-selective inhibitors and a therapeutic strategy involving combined
targeting of BD1-induced epigenetic reprogramming and glycolysis pathways
for the management of pancreatic cancer.