Title:Pharmacological Intervention at CCR1 and CCR5 as an Approach for Cancer: Help or Hindrance
Volume: 14
Issue: 13
Author(s): Angela Karash, Maria R. Mazzoni and Annette Gilchrist
Affiliation:
Keywords:
Cancer, CCL3, CCL5, CCR1, CCR5, chemokine receptor, G protein, G protein coupled receptor, metastasis, polypharmacology.
Abstract: While a number of agents directed at chemokine receptors have entered clinic trials, the vast majority of these
have failed, and the enthusiasm for this class of drugs has been attenuated. To date, there are two drugs that inhibit
chemokine receptors approved by the FDA. The first to be approved in 2007 was maraviroc (brand name Selzentry, or
Celsentri outside the US) which targets CCR5 and is used for the treatment of HIV infection. The second is plerixafor
(Mozobil) which was approved in 2008, targets CXCR4, and is used for the mobilization of hematopoietic stem cells. This
review will focus on the CC chemokine receptors CCR1 and CCR5. These G protein coupled receptors are both activated
by a relatively large number of chemokines, most of which overlap. While most of the drugs for CCR1 have been assessed
in the context of autoimmune diseases like multiple sclerosis and rheumatoid arthritis, and those for CCR5 were
examined for HIV-infection, we review the role of these receptors in relation to cancer. Recently introduced pharmacophores
that serve as agonists or antagonists for the receptors are presented. Efforts to exploit polypharmacology approaches
using promiscuous compounds that target more than one receptor are also considered.
