Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline

Abstract

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton’s tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood–brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

Modern concept of autoimmunity in rheumatology

“…С расшифровкой эффектов блокирования ИФН типа I и некоторых других цитокинов связано расширение показаний к применению ингибиторов JAK [244,[264][265][266]. Патогенетическим обоснованием для применения ингибиторов JAK при аутоиммунных заболеваниях является блокирование широкого спектра «патогенетически значимых» цитокинов, включая ИФН типа I, а также ИЛ-12, ИЛ-23, ИЛ-6, ИЛ-10, ИЛ-21, гранулоцитарно-макрофагальный колониестимулирующий фактор (ГМ-КСФ) и модуляция активности В-клеток [267].…”

Outlook of the jakinibs in systemic lupus erythematous after baricitinib failed

“…pathophysiology of many immune-mediated conditions, 1,2 antagonizing the JAKs is an attractive therapeutic approach. The jakinibs are small molecules that selectively block the actions of the JAKs.…”

“…These include iberdomide (a cereblon E3 ligase modulator), orelabrutinib (a Bruton's tyrosine kinase inhibitor), zetomipzomib (a selective immunoproteasome inhibitor), and afimetoran (a toll-like receptor inhibitor). 1 It is hoped that more therapeutic options would soon be available for patients with SLE so that the prognosis of the disease can be further improved.…”

“…The Janus kinase‐signal transducer and activator of transcription (JAK–STAT) is an important intracellular pathway that transduces downstream signals from multiple cytokines, hormones, and hemopoietic growth factors. As these mediators are relevant to the pathophysiology of many immune‐mediated conditions, 1,2 antagonizing the JAKs is an attractive therapeutic approach. The jakinibs are small molecules that selectively block the actions of the JAKs 3 .…”

“…While we keep our finger crossed for the phase III results of deucravacitinib (POETYK SLE‐1 and SLE‐2), other targeted small molecules have reported encouraging preliminary results in SLE. These include iberdomide (a cereblon E3 ligase modulator), orelabrutinib (a Bruton's tyrosine kinase inhibitor), zetomipzomib (a selective immunoproteasome inhibitor), and afimetoran (a toll‐like receptor inhibitor) 1 . It is hoped that more therapeutic options would soon be available for patients with SLE so that the prognosis of the disease can be further improved.…”