Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia

The epigenetic target CREB (cyclic-AMP responsive element
binding
protein) binding protein (CBP) and its homologue p300 were promising
therapeutic targets for the treatment of acute myeloid leukemia (AML).
Herein, we report the design, synthesis, and evaluation of a class
of CBP/p300 PROTAC degraders based on our previously reported highly
potent and selective CBP/p300 inhibitor 5. Among the
compounds synthesized, 11c (XYD129) demonstrated high
potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen).
The compound effectively degraded CBP/p300 proteins and exhibited
greater inhibition of growth in acute leukemia cell lines compared
to its parent compound 5. Furthermore, 11c demonstrated significant inhibition of tumor growth in a MOLM-16
xenograft model (TGI = 60%) at tolerated dose schedules. Our findings
suggest that 11c is a promising lead compound for the
treatment of AML.