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

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

  • J Med Chem. 2023 Oct 12;66(19):13530-13555. doi: 10.1021/acs.jmedchem.3c00829.
Jinxin Che 1,  Shaowei Bing 2,  Jialiang Lu 1,  Zegao Jin 1,  Jian Gao 1,  Haichao Sheng 3,  Dan Li 1,  Bo Yang 2 4,  Qiaojun He 2 4 5,  Meidan Ying 2 5 6,  Xiaowu Dong 1 4 5 7
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
  • 4 Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310058, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou 310058, China.
  • 6 Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Hangzhou 310052, China.
  • 7 Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
PMID: 37749892 DOI: 10.1021/acs.jmedchem.3c00829
Abstract

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.

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