Rapid Identification of a Potent, Selective, and Orally Active p300/CBP Bromodomain Inhibitor Bearing an Imidazo[1,2- a ]pyridine Scaffold via a Highly Efficient Four-Step Synthesis

]pyridine library for rapid screening. Among these compounds, CZL-105 emerges as a promising p300/CBP bromodomain inhibitor. It exhibits potent activity against p300 and CBP while sparing BET and demonstrates strong antiproliferative potency in OPM-2 multiple myeloma cells. Acceptable metabolic stability and pharmacokinetics support once-daily oral dosing, leading to significant tumor growth inhibition (TGI = 61%) in an OPM-2 xenograft model. These results position CZL-105 as a promising lead compound for further development. This work combines a rational design strategy and efficient chemical synthesis, accelerating the discovery of novel p300/CBP bromodomain inhibitors.