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Updated: Jun 28, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong In Vivo Antitumor Activity
Jiankang Hu1,2, Hongrui Xu3,4, Tianbang Wu1,5
1China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou 510530, China.
Abstract:
The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC50 values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.
Insights
New proteolysis targeting chimeras (PROTACs) effectively degrade CBP/p300 proteins, inhibiting acute myeloid leukemia (AML) cell growth. These compounds show significant antitumor efficacy in preclinical models, offering promising leads for cancer therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- CREB-binding protein (CBP) and p300 are transcriptional coactivators and therapeutic targets in cancers like acute myeloid leukemia (AML).
- Targeting CBP/p300 degradation offers a novel therapeutic strategy for cancer treatment.
Purpose of the Study:
- To design, synthesize, and evaluate novel cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs).
- To assess the efficacy of these PROTACs in inhibiting cancer cell growth and degrading target proteins.
Main Methods:
- Synthesis of a series of CRBN-recruiting CBP/p300 PROTACs based on the CCS1477 inhibitor scaffold.
- In vitro evaluation of compound efficacy, including cell growth inhibition (IC50 values) and protein degradation assays.
- In vivo assessment of antitumor efficacy using a relevant xenograft model.
Main Results:
- Compounds 14g (XYD190) and 14h (XYD198) demonstrated potent inhibition of AML cell growth with low nanomolar IC50 values.
- 14g and 14h effectively and selectively degraded CBP and p300 proteins in a CRBN- and proteasome-dependent manner.
- Significant tumor growth inhibition (88% and 93% for 14g and 14h, respectively) was observed in the MV4;11 xenograft model.
Conclusions:
- Novel CRBN-recruiting CBP/p300 PROTACs, 14g and 14h, exhibit potent anti-AML activity and induce target protein degradation.
- These compounds represent promising lead candidates for further development in human cancer treatment.
- The findings support the therapeutic potential of targeting CBP/p300 via PROTACs in oncology.
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