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Deep learning model enables the discovery of a novel BET inhibitor YD-851
Hongyin Sun1, Guoli Xiong2, Xin Li3
1School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510080, China; Affiliated Fengxian Hospital, Southern Medical University, Fengxian, Shanghai 201400, China.
Abstract:
BET inhibitor is a novel strategy in tumor therapy based on targeting epigenetic mechanism. In recent decades, dozens of clinical trials have been conducted to validate the potential efficacy of the first-generation BET inhibitors in refractory cancer and non-cancerous ailments. However, limited efficacy and significant toxicity were observed in clinical trials for treating solid tumors. Here, we proposed a novel inhibitor strategy as well as an effective and low toxicity agent that can effectively kill tumor cells and exhibited low toxicity. A ring-closure scaffold hopping approach and high-precision deep learning models was leveraged to furnish a series of rationally designed carboline derivatives as desired BET inhibitors. These most potent compounds were synthesized by an efficient and facile multistep route. Subsequent evaluations identified a potent BET inhibitor YD-851 and it can effectively inhibit tumor cell proliferation. In addition, YD-851 causes tumor shrinkage and significantly suppresses tumor growth in multiple xenograft solid tumor models. Moreover the results of toxicity texting and pharmacokinetic properties support further development of YD-851. We obtain an effective and low toxicity preclinical candidate for BET inhibitor to treat solid tumors. And the success of our strategy encourages the implementation of similar methods in the drug discovery of other targets.
Insights
A novel Bromodomain and Extra-Terminal (BET) inhibitor, YD-851, effectively targets solid tumors with low toxicity. This breakthrough offers a promising new strategy for cancer therapy, overcoming limitations of earlier BET inhibitors.
Area of Science:
- Oncology
- Medicinal Chemistry
- Epigenetics
Background:
- Bromodomain and Extra-Terminal (BET) inhibitors represent a novel epigenetic strategy for tumor therapy.
- First-generation BET inhibitors have shown limited efficacy and significant toxicity in clinical trials for solid tumors.
- There is a need for effective, low-toxicity BET inhibitors for solid tumor treatment.
Purpose of the Study:
- To develop a novel, effective, and low-toxicity BET inhibitor for solid tumor therapy.
- To identify potent carboline derivatives as BET inhibitors using scaffold hopping and deep learning.
- To evaluate the preclinical efficacy and safety of a lead compound, YD-851.
Main Methods:
- Utilized a ring-closure scaffold hopping approach combined with deep learning models for inhibitor design.
- Synthesized a series of rationally designed carboline derivatives.
- Evaluated the efficacy of YD-851 in inhibiting tumor cell proliferation and suppressing tumor growth in xenograft models.
- Assessed toxicity and pharmacokinetic properties of YD-851.
Main Results:
- Identified YD-851 as a potent BET inhibitor.
- YD-851 effectively inhibited tumor cell proliferation in vitro.
- YD-851 demonstrated significant tumor shrinkage and growth suppression in multiple solid tumor xenograft models.
- YD-851 exhibited favorable toxicity and pharmacokinetic profiles, supporting further development.
Conclusions:
- YD-851 is a promising preclinical candidate for BET inhibitor therapy in solid tumors.
- The developed strategy of scaffold hopping and deep learning is effective for discovering novel drug candidates.
- This approach holds potential for drug discovery targeting other therapeutic areas.
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