An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma

  • Cell Rep. 2026 Jun 23;45(6):117464. doi: 10.1016/j.celrep.2026.117464.
Praveen Kumar Tiwari  1 ,  Bomin Ku  1 ,  Drew A Harrison  2 ,  Sarah Rizvi  2 ,  Samuel Ojeda  2 ,  Jessica Duffy  2 ,  Leonie Cluse  3 ,  Jennifer R Devlin  3 ,  Nenad Bartonicek  3 ,  Olga Motorna  3 ,  Ann-Sophie Koglin  2 ,  Barbara Karakyriakou  2 ,  Kaitlyn Gagnon  2 ,  Ramya S Iyer  2 ,  Regina Egan  2 ,  Pat Greninger  2 ,  Lauren Benz  2 ,  Caroline Greco  2 ,  Julia Norton  2 ,  Amruth Kumar  2 ,  Eric F Zaniewski  2 ,  Soroush Hajizadeh  2 ,  Robert Morris  2 ,  Genna Mullen  2 ,  Ajinkya S Kawale  1 ,  Sangwon Min  2 ,  Sai Reddy Doda  1 ,  Raghu Vannam  1 ,  Lee Zou  1 ,  Wilhelm Haas  1 ,  Abner Louissaint Jr  1 ,  Ricky W Johnstone  3 ,  Christopher J Ott  4
Affiliations
  • 1. Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 2. Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA.
  • 3. Peter MacCallum Cancer Center, Laboratory Research Division, Parkville, VIC 3052, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia.
  • 4. Krantz Family Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 42228563 DOI: 10.1016/j.celrep.2026.117464
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.

Keywords
CBP; CP: cancer; CP: genomics; KAT; degrader; enhancer; histone acetyltransferase; lysine acetyltransferase; multiple myeloma; near-linkerless PROTAC; p300.
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