Multiple myeloma (MM) is an incurable cancer resulting from malignant transformation of plasma cells, terminally differentiated B cells that reside in the bone marrow (BM). The BM allows reciprocal interactions between the different components of the BM microenvironment and the MM cells necessary for migration, differentiation, proliferation and survival of the malignant plasma cells leading to osteolytic bone disease. The chemokine CCL3 appears to play a role in promoting differentiation and increased activity of osteoclasts. Expressed by both myeloma cells, and osteoclasts, CCR1 and CCR5 are the primary chemokine receptors for CCL3.  This study focused on synthesis and evaluation  of more than twenty novel small molecules via competitive binding assays that utilized membranes prepared from a MM cell line. These molecules were based on a previously published series of CCR1 antagonists defined by a unique pyrrolidine motif. Compounds inhibiting binding of 125I-CCL3 were further  evaluated using  functional cell based assays. 

Synthesis and evaluation of pyrrolidine derivatives as CCR1 antagonists for in vitro inhibition of multiple myeloma

244th National Meeting (2012)

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