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

Tiwari, PK; Ku, B; Harrison, DA; Rizvi, S; Ojeda, S; Duffy, J; Cluse, L; Devlin, JR; Bartonicek, N; Motorna, O; Koglin, AS; Karakyriakou, B; Gagnon, K; Iyer, RS; Egan, R; Greninger, P; Benz, L; Greco, C; Norton, J; Kumar, A; Zaniewski, EF; Hajizadeh, S; Morris, R; Mullen, G; Kawale, AS; Min, S; Doda, SR; Vannam, R; Zou, L; Haas, W; Louissaint, A, Jr; Johnstone, RW; Ott, CJ

Author(s): Tiwari, PK; Ku, B; Harrison, DA; Rizvi, S; Ojeda, S; Duffy, J; Cluse, L; Devlin, JR; Bartonicek, N; Motorna, O; Koglin, AS; Karakyriakou, B; Gagnon, K; Iyer, RS; Egan, R; Greninger, P; Benz, L; Greco, C; Norton, J; Kumar, A; Zaniewski, EF; Hajizadeh, S; Morris, R; Mullen, G; Kawale, AS; Min, S; Doda, SR; Vannam, R; Zou, L; Haas, W; Louissaint, A, Jr; Johnstone, RW; Ott, CJ;
Details: Publication Year 2026-06-02,Volume 45,Issue #6,Page 117464
Journal Title: Cell Reports
Publication Type: Research 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.
Publisher: Cell Press
Keywords: Cbp; CP: cancer; CP: genomics; Kat; degrader; enhancer; histone acetyltransferase; lysine acetyltransferase; multiple myeloma; near-linkerless PROTAC; p300
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1016/j.celrep.2026.117464
Open Access at Publisher's Site: https://doi.org/10.1016/j.celrep.2026.117464
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-23 03:42:09

Last Modified: 2026-06-23 03:42:14