An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma
Year: 2026
Type: article
Abstract: The enhancer lysine acetyltransferases CBP/p300 are compelling targets for multiple myeloma therapy. Chemical inhibition of these multidomain factors, either through the bromodomain or the catalytic acetyltransferase domain, show promising activity in pre-clinical models. Chemical degradation is the only modality that can completely disrupt all functional domains. Our previous attempts to induce CBP/p300 targeted degradation led to a potent tool compound, dCBP-1. Here we comprehensively demonstrate across a large panel of cell lines how CBP/p300 degradation compares to inhibition, with pronounced selective antiproliferative activity toward multiple myeloma. We use chemical linker optimization strategies to create a compound with better pharmacokinetic properties. Through these we define an advanced analog of dCBP-1, dCBP-30, that has improved potency and improved in vivo properties including oral bioavailability. dCBP-30 led to potent and sustained loss of CBP and p300, potent inhibition of several myeloma-specific dependency programs, and elicits tumor reduction in xenograft models.
Source: Cell Reports
Authors: Praveen Kumar Tiwari, Bomin Ku, Drew A. Harrison, Sarah Rizvi, Samuel Ojeda, Jessica Duffy, Leonie Cluse, Jennifer R. Devlin, Nenad Bartonicek, Olga Motorna, Ann-Sophie Koglin, Barbara Karakyriakou, Kaitlyn Gagnon, Ramya S. Iyer, Regina Egan, Pat Greninger, Lauren Benz, Caroline Greco, Julia Norton, Amruth Kumar, Eric F. Zaniewski, Soroush Hajizadeh, Robert Morris, Genna Mullen, Ajinkya S. Kawale, Sangwon Min, Sai Reddy Doda, Raghu Vannam, Lee Zou, Wilhelm Haas, Abner Louissaint, Ricky W. Johnstone, Christopher J. Ott
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: LC/MS Replacement for Institute for Innovation in Imaging Core Facility., Electronics Upgrade for 11.7 T, Targeting chromatin acetylation factors in multiple myeloma, A Real-Time AI-Driven High-Throughput Proteomics Data Acquisition Method for Clinical Applications, Dana-Farber/Harvard Cancer Center
OpenAlex ID: W7163205579