Table 1.

Selected STAT3 inhibitors showing in vitro and/or clinical efficacy against multiple myeloma. The mechanism by which STAT3 is inhibited by the compound as well as evidence for in vitro synergy with known anti myeloma therapy and clinical evidence where applicable are presented. STAT3 (Signal transducers and activators of transcription 3), PIAS3 (protein inhibitor of activated STAT3), SHP-1 (SRC homology 2 domain containing phosphatase 1) PTEN (phosphatase and tensin homolog). MM (multiple myeloma), NA (data not available), SH2 (src homology 2), JAK (janus associated kinase), IL-6 (Interleukin 6).

STAT-3 Inhibitor	Mechanism of STAT3 Inhibition	In Vitro Synergy with Known Anti MM Agents	Clinical Evidence of Efficacy	Reference
Ruxolitinib	Indirect, via JAK inhibition	Bortezomib Lenalidomide	Phase 1 clinical trial	Chen et al. 2014 [70] Berenson et al. 2018 [71]
Tofacitinib	Indirect, via JAK inhibition	Venetoclax	NA	Lam et al. 2018 [72]
INCB16562	Indirect, via JAK1 inhibition	Bortezomib Melphalan	NA	Li et al. 2010 [74]
YL064	Direct, STAT3 SH2 domain inhibitor	NA	NA	Wang et al. 2018 [78]
OPB51602	Direct, STAT3 SH2 domain inhibitor	NA	Phase 1 clinical trial. Excessive toxicity and unfavourable pharmacokinetic profile	Ogura et al. 2015 [83]
Hydrocalamenene	Indirect, JAK1,2, SRC inhibition. Upregulation of PIAS3	Bortezomib	NA	Nam et al. 2014 [89]
Genipin	Indirect, SRC inhibition, SHP-1 upregulation	Bortezomib, thalidomide, paclitaxel	NA	Lee et al. 2011 [91]
Icariside II	Indirect, JAK2, SRC inhibition. Upregulation of SHP-1 and PTEN	Bortezomib, Thalidomide	NA	Kim et al. 2011 [92]
Niclosamide	Indirect inhibition by inhibiting IL-6 mediated phosphorylation of STAT3	NA	NA	Khanim et al. [77]
Asiaticoside	Reduced phosphorylation of STAT3, mechanism not known	NA	NA	Yingchun et al. [96]
Gossypol	Inhibition of IL-6 signalling	NA	NA	Sadahira et al. [97]
LCL161	Not known, synergism with JAK2 inhibitor against MM cell lines	NA	NA	Ramakrishnan et al. [76]