Chemokine CXCR4 receptor modulators and uses related thereto
Patent Number: US9545403

Executive Summary:
  • Invention Type: Therapeutic
  • Patent Status: US grant
  • Patent Link: https://patents.google.com/patent/US9545403/
  • Research Institute: Emory University
  • Disease Focus: Cancer, HIV
  • Basis of Invention: A chemical inhibitor of a T cell receptor CXCR4
  • How it works: CXCR4 is a major co-receptor for HIV entry to T cells. CXCR4 is also expressed in metastatic breast cancer and lymphomas and promotes migration of metastatic cells
  • Lead Challenge Inventor: Dennis C. Liotta
  • Inventors: Lawrence J. Wilson, John Wiseman, Dennis C. Liotta, Michael G. Natchus 
  • Development Stage: Pre-clinical: in vitro data in cancer cell lines
  • Novelty:
    • The proposed therapeutic agent is a chemical compound, distinct from the other chemical and biological (antibody, peptide, or siRNA) CXCR4 antagonists, which are being developed by others
    • The distinct feature of this class of therapeutics is their potentially lower toxicity
  • Clinical Applications:
    • Metastatic breast cancer
    • Metastatic lymphomas
    • HIV infection prevention and treatment

General Description:
This invention proposes to use chemical antagonists of CXCR4, a major HIV co-receptor, to treat cancers. CXCR4 is involved in migration of cancer cells and promotes vascularization necessary for metastasis. All the CXCR4 antagonists that were chronically dosed in clinical trials before 2009 have been withdrawn because of unmanageable toxicities (ref. 1). The low metabolic liability potential has been reported for the compounds (ref. 2), suggesting their potentially low toxicity.

Scientific Progress:
Pharmacokinetic experiments were performed in rats and mice; some compounds were shown to have oral bioavailability (ref 2).

Future Directions:
  • Pre-clinical testing of the compounds for toxicity and anti-tumor activity
 
Strengths:
  • CXCR4 is a promising therapeutic target for various cancers
  • The synthesis procedures for CXCR4 antagonists are well established

Weaknesses:
  • Limited characterization of anti-cancer potential of the compounds described in the patent

Patent Status:
Publications:
1: Mosley CA, Wilson LJ, Wiseman JM, Skudlarek JW, Liotta DC. Recent patents regarding the discovery of small molecule CXCR4 antagonists. Expert Opin Ther Pat. 2009 Jan;19(1):23-38. doi: 10.1517/13543770802553483. Review. PubMed PMID:19441896.
 
2: Truax VM, Zhao H, Katzman BM, Prosser AR, Alcaraz AA, Saindane MT, Howard RB, Culver D, Arrendale RF, Gruddanti PR, Evers TJ, Natchus MG, Snyder JP, Liotta DC, Wilson LJ. Discovery of tetrahydroisoquinoline-based CXCR4 antagonists. ACS Med Chem Lett. 2013 Sep 5;4(11):1025-30. doi: 10.1021/ml400183q. eCollection 2013 Nov 14. PubMed PMID: 24936240; PubMed Central PMCID: PMC4057008.

Inventor Bio: Dennis C. Liotta
http://chemistry.emory.edu/home/people/faculty/liotta-dennis.html