Discovery of Novel Oxazepine Derivatives as Akt/ROCK Inhibitors for Growth Arrest and Differentiation Induction in Neuroblastoma Treatment.

Patients with high-risk neuroblastoma face limited treatment choices, typically involving a combination of cytotoxic and differentiation maintenance therapies due to a scarcity of drugs. Evidence suggests that targeted inhibitors may provide opportunities for inducing neuroblastoma differentiation while inhibiting proliferation. Here, we demonstrate the synergistic effect of inhibiting Akt and ROCK in antineuroblastoma and present the design and discovery of a new Akt/ROCK inhibitor, B12. It displays strong antiproliferative effects and excellent differentiation inducing activity against Neuro2a cells. Treatment with B12 results in the arrest of G0/G1 cell cycles, a significant decrease in N-myc protein level, and an increase in differentiation markers. The administration of B12 effectively suppresses xenograft tumor growth and promotes differentiation. Overall, the discovery of B12 based on the Akt/ROCK dual inhibition strategy may provide hope for the development of more effective and targeted therapies for this challenging disease.

Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity.

Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound 2 is selected for further optimization for overcoming the disadvantages of compound 1, including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and molecular dynamics simulation lead to the identification of Hu7691 (B5) that achieves a 24-fold selectivity between Akt1 and Akt2. Hu7691 exhibits low activity in inducing HaCaT apoptosis, promising kinase selectivity, and excellent anticancer cell proliferation potencies. Based on the superior results of safety property, pharmacokinetic profile, and in vivo efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of Hu7691.

Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents.

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the HipHop program by screening a database containing compounds which were designed based on the known structure-activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which showed a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC50 value of 14.8 µM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 µg ml-1).