Pharmacological intervention at CCR1 and CCR5 as an approach for cancer: help or hindrance.

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.

Therapeutic potential of CCR1 antagonists for multiple myeloma.

The chemokine receptor CCR1 has been the target of intensive research for nearly two decades. Small-molecule antagonists were first reported in 1998 and, since then, many inhibitors for CCR1 have been brought forth. Yet, with all the money and time spent, to date, no small-molecule antagonists have successfully moved past Phase II clinical trials. With the current advancement of CCR1 antagonists by Bristol-Myers Squibb and Chemocentrix, there has been renewed interest. In this review, we present an overview of CCR1, its activating ligands, methods of signaling, and downstream response. We discuss studies that indicate CCR1 plays an important role in multiple myeloma and the underlying molecular mechanisms. Finally, we present an overview of the clinical and preclinical compounds for CCR1. We address individual structures, discuss their pharmacological précis, and summarize the published evidence to assess their value for use in multiple myeloma.