Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues
Abstract
Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)–based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo–electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (13)
Samuel Ojeda
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Meng Wang
Kheewoong Baek
Department of Cancer Biology, Dana–Farber Cancer Institute, Boston, MA 02215, USA.
Wallace Bourgeois
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Alba Sommerschield
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Hong Yue
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Rebecca J. Metivier
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Panos Karagiannis
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Talya S. Levitz
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Yuan Xiong
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Katherine A. Donovan
Scott A. Armstrong
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
Eric S. Fischer