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, .

Discovery of -((3,4)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1-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 is selected for further optimization for overcoming the disadvantages of compound , including high Akt2 inhibition and high toxicity against HaCaT keratinocytes.

Discovery of 5,6-Bis(4-methoxy-3-methylphenyl)pyridin-2-amine as a WSB1 Degrader to Inhibit Cancer Cell Metastasis.

The gain of cell motility is an essential prerequisite for cancer metastasis. The ubiquitin ligase subunit WD repeat and SOCS box-containing 1 (WSB1) has been demonstrated to regulate hypoxia-driven tumor cell migration. However, there is still a lack of methods for discovering inhibitors targeting the WSB1 axis.

Development of differentiation modulators and targeted agents for treating neuroblastoma.

Neuroblastoma (NB) is one of the most common pediatric malignancies. Easy metastasis, poor prognosis, and a high degree of heterogeneity of NB hinder its successful treatment. Several different therapeutic strategies have been developed to overcome these problems, including differentiation and targeted therapy.

Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design.

A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, , that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure-activity relationship of compound , involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative . showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles.