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Discovery of Exceptionally Potent, Selective, and Efficacious PROTAC Degraders of CBP and p300 Proteins
Junius Eugene Thomas1,2, Mi Wang2, Wei Jiang2
1Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48104, United States.
Abstract:
The histone acetyltransferase CREB-binding protein (CBP) and its paralogue p300 protein are key transcriptional coactivators and attractive cancer therapeutic targets. We describe herein our design, synthesis, and extensive evaluation of exceptionally potent PROTAC degraders of CBP/p300, exemplified by JET-209 (24). This compound, JET-209, achieved a half-maximal degradation (DC50) value of 0.05 nM for CBP and 0.2 nM for p300 with maximum degradation (Dmax) >95% for both proteins in the RS4;11 leukemia cell line after 4 h of treatment. JET-209 achieved subnanomolar to low nanomolar DC50 values in the inhibition of cell growth in several representative acute leukemia cell lines and was much more potent than CBP/p300 bromodomain and catalytic domain inhibitors. JET-209 effectively inhibited tumor growth in xenograft tumor models at tolerated dose schedules. JET-209 is a promising lead compound for further evaluation and optimization toward the development of a CBP/p300 degrader for the treatment of human cancers.
Insights
Researchers developed JET-209, a potent PROTAC degrader targeting CREB-binding protein (CBP) and p300. This compound effectively inhibits leukemia cell growth and tumor progression, showing promise for cancer therapy.
Area of Science:
- Molecular Biology
- Medicinal Chemistry
- Oncology
Background:
- CREB-binding protein (CBP) and its paralogue p300 are crucial transcriptional coactivators.
- Dysregulation of CBP/p300 is implicated in various cancers, making them attractive therapeutic targets.
Purpose of the Study:
- To design, synthesize, and evaluate novel PROTAC degraders targeting CBP/p300.
- To assess the efficacy of these degraders in preclinical cancer models.
Main Methods:
- Design and synthesis of PROTAC molecules.
- In vitro assessment of protein degradation (DC50, Dmax) in leukemia cell lines.
- Evaluation of anti-proliferative effects on cancer cell lines.
- In vivo efficacy studies in xenograft tumor models.
Main Results:
- JET-209 demonstrated exceptionally potent degradation of CBP (DC50=0.05 nM) and p300 (DC50=0.2 nM) with >95% degradation at 4 hours.
- JET-209 exhibited subnanomolar to low nanomolar potency in inhibiting leukemia cell growth, surpassing existing CBP/p300 inhibitors.
- Significant inhibition of tumor growth was observed in vivo at well-tolerated doses.
Conclusions:
- JET-209 represents a highly potent PROTAC degrader of CBP/p300.
- JET-209 shows significant preclinical efficacy in leukemia models.
- This compound is a promising lead for developing novel CBP/p300-targeted cancer therapeutics.
