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.
Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL 60515, USA.
Angela R
AR
Karash
Annette
A
Gilchrist
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D054389:Receptors, CCR1