Table 2.
Properties of potential druggable targets in RA.
| Leads from Multi-omics | Pathology | Cell Type Expression | Signaling pathway | Animal Model | 3D Structures | Clinical Status |
|---|---|---|---|---|---|---|
| MAP3K8/TPL2 (genomics, multiple evidences) | Cell survival, production of inflammatory, degradative mediators, angiogenesis factors | Synovial fibroblasts, myeloid cells, neutrophils | MAPK pathways (ERK, p38 and JNK), NFĸB signaling |
Tpl2 knockdown in CIA mice; inhibition in DSS-induced colitis mice model |
5IU2 (catalytic site with adjacent selectivity pocket due to unique kinase domain structure) |
SAR studies of preclinical molecules for RA; Clinical molecule for Ulcerative colitis |
| PADI4 (genomics, transcriptomics, epigenomics) | NET formation, inflammation, regulation of T-cell mediated immune response | Neutrophils, monocytes | Citrullination pathway | Inhibitor study in CIA murine model | 4X8G, 4X8C (catalytic site) | Preclinical molecules for RA, SLE |
| SHP2 (genomics and epigenomics) | Survival and invasiveness of synovial lining FLS | FLS, myeloid cells | TNF-induced signaling through FAK and downstream MAPK (JNK, p38 and ERK) activation | Heterozygous PTPN11 deletion study in K/BxN serum transfer arthritis in mice |
5EHR (allosteric site with hydrophobic subpocket can be targeted for selectivity) | Preclinical non-competitive inhibitor for RA; Clinical molecules for solid tumors |
| PI3Kδ (epigenomics) | Synovial hyperplasia, cell mobility and activation | FLS in intimal lining, neutrophils, mast cells, B-cell, T-cell | AKT and RAC signaling | Inhibitor study in CIA rat model | 4XE0 (Hydrophobic pocket adjacent to hinge region for selective lead design) | SAR studies in RA; FDA approved inhibitor for cancer; Phase-2 inhibitors for asthma, COPD |
| HDAC3 (epigenomics) | Inflammatory gene expression | FLS, M1 macrophages, monocytes | TLR signaling | Only in vitro studies | 4A69 (apo-structure, conformationally flexible site) | SAR studies of preclinical molecules |
| BRD2/4 (epigenomics, genomics) | Transcriptional activation of MMP, IL-6,8; angiogenesis | FLS, macrophages, endothelial cells | TNF-α/IL-1β/TLR signaling, VEGF-PAK1 signaling | Inhibitor/siRNA study in CIA model | 5EK9 (BRD2), 4MR4 (BRD4), BD2 domain selective; dual kinase/BRD inhibitors need to be explored | SAR studies of preclinical molecules for RA; 11 clinical trial molecules in other diseases |
| CHKα (metabolic reprogram) | Cell migration and proliferation, inflammation | FLS, macrophages | MAPK and PI3K/AKT signaling | Inhibitor study in K/BxN serum transfer arthritis in mice | 5AFV, 4DA5 (ATP binding site), 5W6O (allosteric site) |
Preclinical molecules for RA; Clinical molecules for solid tumors |
| SPK1 (metabolic reprogram) | Synovial hyperplasia, leucocyte infiltration inflammation | FLS | MAPK ERK, PI3K/AKT signaling | Knockdown in CIA, AIA | 3VZC, 4V24 (catalytic site with selective features of C4 domain) | SAR studies of preclinical molecules for RA |
| HK2 (metabolic reprogram) | Cell activation, invasive phenotype | Synovial lining FLS | Inducible glucose metabolism | Deletion in K/BxN serum transfer arthritis model | 5HG1, 5HFU (C-terminal catalytic pocket) | SAR studies of preclinical molecules for cancer |
MAPK, mitogen-activated protein kinase; SAR, structure-activity relationship; PADI4, peptidyl arginine deiminase 4; SLE, systemic lupus erythematosus; FLS, fibroblast-like synoviocytes; TNF, tumor necrosis factor; SHP2, Src homology-2 domain-containing protein tyrosine phosphatase-2; PI3Kδ, phosphatidylinositide 3-kinase delta; HDAC3, histone deacetylase 3; BRD2/4, bromodomain and extra-terminal proteins; CHKa, choline kinase alpha; SPK1, sphingosine kinase 1; HK2, hexokinase 2; CIA, collagen-induced arthritis; AIA, antibody induced arthritis.