Quinoxaline compounds and uses thereof
Patent Number: US20130289041

Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: Granted
  • Patent Link: https://patents.google.com/patent/US20130289041/
  • Research Institute: University of Nebraska Medical Center
  • Disease Focus: Resistant Mantle Cell Lymphoma, Pancreatic Cancer, NH Lymphoma, Colon Cancer
  • Basis of Invention: NFKB and IKKB signalling promote angiogenesis and tumor progression in Resistant Mantle Cell Lymphoma cancer cells, four isoforms of IKKB exist to date there are no currently inhibitors or antibodies to bind, this lead to the design and chemical synthesis of inhibitors of IKKB using quinoxaline compounds, a drug library screen of 100 compounds was tested with different binding affinities and IC50 on IKKB activity was measured, from this library a compound named 13-197 was effective to induce apoptosis, TNF increase and IKK-B phosphorylation inhibition in the range of 10 μM IC50, furthermore 13-197 showed to decrease significantly mTOR activation in MCL cells
  • How it works: Inhibition of IKKB phosphorylated state by the binding of small molecule 13-197 inhibiting mTOR downstream signaling resulting in enhanced cell cytotoxicity of MCL therapy resistant to chemotherapy. In addition, 13-197 showed reduction in TNF alfa activation and induced apoptotic activity by increasing p62 and BCL levels
  • Lead Challenge Inventor: Amarnath Natarajan
  • Inventors: Amarnath Natarajan, Qianyi Chen, Vashti C. Bryant, Rajkumar Rajule
  • Development Stage: Pre-clinical stage in vitro results
  • Novelty: IKKB inhibitors to treat Resistant Mantle Cell Lymphoma, and NH lymphoma resistant cell lines
  • Clinical Applications:
    • Resistant Mantle Cell Lymphoma, Pancreatic cancer, other Lymphomas
 
General Description:
The invention described novel synthesis of quinoxaline derived analogues to inhibit IKKB. The inventor created a drug library of more than 50 potential analogues and screened for IKKB binding. From the screening one compound 13-197 was effective in increasing cell cytotoxicity in MCL therapy resistant cancer cell lines and inhibit mTOR downstream signaling as an additional effect. The screen was made in vitro. Further in vivo studies are needed to warrant effectiveness of 13-197as a potential anticancer agent in cancers with increased NFKB and IKKB signaling.
 
Scientific Progress:
Inhibiting IKKB and mTOR activation by quinoxaline based compounds

Future Directions:
  • Preclinical animal models
 
Strengths:
  • Novel inhibition of two pathways important for cancer progression IKKB and mTOR signaling

Weaknesses:
  • The patent only demonstrates in vitro data
 
Patent Status: 
Publications:
Chaturvedi NK, Rajule RN, Shukla A, Radhakrishnan P, Todd GL, Natarajan A, Vose JM, Joshi SS. Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach. Mol Cancer Ther. 2013 Oct;12(10):2006-17. doi: 10.1158/1535-7163.MCT-13-0239. Epub 2013 Aug 20. PubMed PMID: 23963361; PubMed Central PMCID: PMC4124828.
 
Inventor Bio: Amarnath Natarajan
https://www.unmc.edu/eppley/about/faculty/natarajan.html