Small molecules in the treatment of systemic lupus erythematosus

Abstract

Advances in the understanding of the cellular biological events that underlie systemic lupus erythematosus (SLE) have led to the identification of key molecules and signaling pathways that are aberrantly expressed. The parallel development of small molecule drugs that inhibit or interfere with the specific perturbations identified, offers perspective for more rational, effective and less toxic therapy. In this review, we present data from preclinical and clinical studies of such emerging novel therapies with a particular focus on kinase inhibitors and other compounds that modulate signal transduction. Moreover, we highlight the use of chromatin-modifying medications, bringing attention to the central role of epigenetics in SLE pathogenesis.

Introduction

The existing therapies for systemic lupus erythematosus (SLE) despite being effective in suppressing disease activity, rarely offer long-term remission; moreover medication-related toxicity contributes to morbidity and mortality [1]. On the other hand, the heterogeneous nature of SLE, calls for personalized treatments based on the molecular identities of subgroups of SLE patients.

The approval of imatinib for the treatment of chronic myelocytic leukemia (CML) [2] has set the stage for developing a new therapeutic paradigm based on the identification and then targeting of the specific molecular pathways that are aberrant in disease (Fig. 1). This novel approach aims at the development of small molecules that inhibit inter- and intra-cellular signaling potentially offering the prospect of rational, individualized and less toxic treatments. In this review we summarize the most recent research on the development of small molecules that target kinases and other signaling molecules that are implicated in SLE pathogenesis or regulate the chromatin structure of pathogenetically important genes in animal models and humans with SLE (Table 1).