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EMBO Mol Med. 2019 Sep 26:e10659. doi: 10.15252/emmm.201910659. [Epub ahead of print]

The novel BET-CBP/p300 dual inhibitor NEO2734 is active in SPOP mutant and wild-type prostate cancer.

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Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, BC, Canada.
Department of Physics, State Key Laboratory of Surface Physics, Fudan University, Shanghai, China.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Phoenix, AZ, USA.
Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
Developmental Therapeutics Consortium, Chicago, IL, USA.
The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Department of Urology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Mayo Clinic Cancer Center, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.


CULLIN3-based E3 ubiquitin ligase substrate-binding adaptor gene SPOP is frequently mutated in prostate cancer (PCa). PCa harboring SPOP hotspot mutants (e.g., F133V) are resistant to BET inhibitors because of aberrant elevation of BET proteins. Here, we identified a previously unrecognized mutation Q165P at the edge of SPOP MATH domain in primary and metastatic PCa of a patient. The Q165P mutation causes structural changes in the MATH domain and impairs SPOP dimerization and substrate degradation. Different from F133V hotspot mutant tumors, Q165P mutant patient-derived xenografts (PDXs) and organoids were modestly sensitive to the BET inhibitor JQ1. Accordingly, protein levels of AR, BRD4 and downstream effectors such as RAC1 and phosphorylated AKT were not robustly elevated in Q165P mutant cells as in F133V mutant cells. However, NEO2734, a novel dual inhibitor of BET and CBP/p300, is active in both hotspot mutant (F133V) and non-hotspot mutant (Q165P) PCa cells in vitro and in vivo. These data provide a strong rationale to clinically investigate the anti-cancer efficacy of NEO2734 in SPOP-mutated PCa patients.


BRD4; CBP/p300; NEO2734; SPOP; prostate cancer

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