Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Prostate cancer is a significant cause of cancer-related mortality.
• Bromodomain and extra terminal domain (BET) proteins are emerging therapeutic targets for castration-resistant prostate cancer.

Purpose of the Study:

• To design and synthesize novel 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as selective inhibitors of bromodomain containing protein 4 (BRD4).
• To evaluate the efficacy of these compounds in preclinical models of prostate cancer.

Main Methods:

• Synthesis of a series of 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives.
• In vitro assays to determine BRD4(1) inhibition potency (IC50) and selectivity against non-BET proteins.
• Assessment of compound effects on prostate cancer cell lines, including cell growth, colony formation, and expression of key genes (androgen receptor, MYC).
• In vivo pharmacokinetic (PK) studies and oral bioavailability assessment of a lead compound.

Main Results:

• Synthesized derivatives potently inhibited BRD4(1) with nanomolar IC50 values.
• Compounds demonstrated high selectivity over most non-BET subfamily members.
• Representative compound 36 significantly suppressed prostate cancer cell growth, colony formation, and expression of androgen receptor (AR), AR-regulated genes, and MYC.
• Compound 36 exhibited a favorable PK profile with 61.54% oral bioavailability in vivo.

Conclusions:

• The novel benzo[b][1,4]oxazin-3(4H)-one derivatives are potent and selective BRD4 inhibitors.
• Compound 36 demonstrates significant preclinical efficacy and favorable pharmacokinetic properties, positioning it as a promising lead for prostate cancer drug development.