Inhibitor class: Natural Products |
Curcumin* | Dietary spice that has been shown to inhibit JAK1, JAK2 and therefore STAT3 tyrosine phosphorylation. | Inhibits AR expression | [131,132,133] |
Guggulsterone | Stimulates tyrosine phosphatases responsible for de-phosphorylation of STAT3. | Causes apoptosis in AR- PC3 cells through STAT3 inhibition. | [134,135,136] |
Capsaicin* | Inhibits JAK1 mediated STAT3 phosphorylation but also induces tyrosine phosphatases. | Induces apoptosis in vitro and in vivo. | [137,138] |
Celastrol | Inhibits IL6 induced JAK2 phosphorylation of STAT3. | Inhibits the TMPRSS-ERG fusion. | [139,140] |
Caffeic acid (CA) CAPE CADPE | Caffeic acid and its derivatives all inhibit STAT3 phosphorylation by blocking JAK2 activity along with other tyrosine kinases like Src. | Anti-proliferative and anti-androgenic activity. | [141,142,143] |
Curcubitacin B E F | Chinese medicine family ranging from Curcubitacin A to T. Curcubitacin B has been studied the most and it prevents STAT3 phosphorylation by inhibiting JAK2. | Curcubitacin E disrupts cytoskeleton in PCa cell lines. | [144,145] |
Cryptotanshinone* | Binds to SH2 domain of STAT3 and prevents dimerization. | Inhibits STAT3 in PCa cell lines and suppresses AR activity, | [146,147] |
3,3′-diindolyl-methane* | DIM has various anti-cancer properties. It inhibits JAK2 function. It is also important to note that DIM has anti-androgen activity. | Heavily tested in PCa, affects AR activity, metastasis, epigenetics, Currently in Phase II clinical trials for PCa. | [148,149,150,151,152,153] |
Emodin | Pugrative resin extracted from rhubarb. Has various pharmacological activities including inhibition of JAK2. | Inhibits PI3K pathway and AR activity in PCa cell lines. | [154,155,156] |
Paclitaxel* | Inhibit STAT3 phosphorylation and STAT3 interaction with tubulin. | Has been tested in many Clinical Trials for CRPC and metastatic PCa. | [157,158] |
Evodiamine | Suppresses pY-STAT3 by inducing expression of tyrosine phosphatase SHP-1. | Causes apoptosis in various PCa cell lines. | [159,160,161] |
Indirubin | Block VEGFR induced phosphorylation of JAK2 and consequently STAT3. | Induces apoptosis and reduces angiogenesis in PCa cell lines via STAT3 inhibition. | [92,162,163] |
Inhibitor class: STAT3 Small Molecule Inhibitors | |
S31-1757 | Binds to the SH2 domain of STAT3. The inhibitor binds to Arg-609 and Lys-591; both sites are essential in recognition and binding to the pTyr-705 residue of STAT3 (dimerization) as well as the pTyr-904 for binding to the gp-130 subunit of the IL-6 receptor as well as other receptors like EGFR. | Not yet tested in PCa | [164] |
Sttatic | Small-molecule that directly binds to the SH2 domain of STAT3 preventing the interaction with the phosphor-tyrosine motif of the neighbouring STAT3. | Not yet tested in PCa | [165] |
STA-21 | Also known as Ochromycinone was discovered through a virtual database screen in silico and was shown to inhibit STAT3 SH2 and phosphor-Tyr interaction. | Tested against some PCa cell lines where it reduces growth through pY-STAT3. | [166,167] |
S31-201 | Benzoic acid that was also discovered through in silico screen also inhibits dimerization of STAT3 through the SH2 domain. | Not yet tested in PCa | [168] |
BP-1-102 | Software designed analog of S31-201 whose structural differences allow it to interact with all 3 strutural sub-pockets in the SH2 domain of STAT3 causing a more potent inhibition of the dimerization. | Not yet tested in PCa | [169] |
LLL12 | Binds directly to Tyr705 of STAT3 to prevent phosphorylation and subsequent dimerization. | Not yet tested in PCa | [170] |
Inhibitor class: Kinase inhibitors | |
SAR302503* | Orally available inhibitor of Janus Kinase 2 (JAK-2). | Reduces tumor growth in vivo through suppression of STAT3. | [171,172] |
LS104 | A non-ATP-competitive small molecule inhibitor of JAK-2. This attribute of LS104 allows it to be used in combination with an ATP-competitive inhibitor for a synergistic effect. | Not yet tested in PCa | [173] |
Atiprimod | Cationic amphiphilic compound that blocks transcription of IL-6 by inhibiting the NFκβ pathway as well as inhibits the phosphorylation of STAT3 at Tyr705 through a separate mechanism. | In clinical trials for Neuroendocrine Carcinoma. Could have implications in PCa. | [174,175,176,177] |
Ruxolitinib (INCB-018242)* | Orally available a JAK1 and JAK2 inhibitor. | Failed Clinical Trials in metastatic PCa. | [124,178] |
Lestaurtinib (CEP-701) | Inhibitor of a few tyrosine kinases including JAK2. It is structurally similar to staurosporine. | Suppresses AR activity. | [179,180] |
Tofacitinib | Primarily a JAK3 inhibitor, but has some activity against JAK1 and therefore reduces pY-STAT3. | Not yet tested in PCa. | [181] |
CYT387* | ATP competitive JAK1 and JAK2 inhibitor. | Not yet tested in PCa. | [182] |
Pacritinib* | Orally available inhibitor for JAK2. | Not yet tested in PCa. | [183] |
Sorafenib* SC-1 SC-49 | Sorafenib and its derivatives are tyrosine kinase inhibitors that affect multiple kinases, including JAK2. They reduce pY-STAT3. | Currently in many clinical trials for metastatic PCa. | [184,185] |
AZD1480* | ATP-competitive JAK2 inhibitor. | Suppresses growth of PCa cell lines. | [186,187] |
Auranofin | A gold compound that inhibits STAT3 phosphporylation through JAK1 and also inhibits NFκβ activity. | Not yet tested in PCa. | [188,189] |
AG-490 | Known as Tyrophostin B42 is a potent inhibitor of Janus Kinase 2 (JAK2). | Induces apoptosis by supressing STAT3 activity. | [190,191,192] |
XZH-5 | Inhibits Tyr705 phosphorylation and dimerization of STAT3 and possibly targets one of the tyrosine kinases responsible for this: mechanism is unknown. | Not yet tested in PCa. | [92,193,194] |
FLLL32 | Derived from Curcumin, this compound prevents phosphorylation of STAT3 by inhibiting JAK2. | Not yet tested in PCa. | [195] |
BMS-911543 | Orally available small molecule JAK2 inhibitor. Active against V617F JAK2 mutants. | Not yet tested in PCa. | [196,197] |
AC-430 | Small molecule JAK2 inhibitor, also active against the V617F mutant. | Not yet tested in PCa. | [1] |
CEP-33779 | Small molecule JAK2 inhibitor. | Not yet tested in PCa. | [198,199,200] |
R723 | Small molecule JAK2 inhibitor, also active against the V617F mutant. | Not yet tested in PCa. | [201,202] |
Inhibitor class: IL-6 Antibodies/Inhibitors | |
Sant7 | superantagonist of the IL-6 receptor capable of blocking all IL-6 receptor activity and therefore the activity of one of its major downstream transcription factors: STAT3. | Sensitizes PCa cell lines to cytotoxic therapy by inhibiting IL6/JAK/STAT3 pathway. | [203,204] |
Tocilizumab | Humanized monoclonal antibody against the human IL-6 receptor. Works against both soluble and membrane bound IL-6R. | Not yet tested in PCa. | [205] |
Siltuximab (CNTO 328)* | Chimeric murine-human monoclonal IL-6 antibody. | Failed Phase II clinical Trials in CRPC. | [127,206] |
Inhibitor class: DNA or RNA targeting | |
Platinum Compounds CPA-1 CPA-7 IS3-295 Carboplatin Oxaliplatin Satraplatin | Complexes like CPA-1, CPA-7 and IS3-295 disrupt the STAT3 interaction with DNA in breast, prostate, lung and skin cancers. The exact site where these complexes bind to STAT3 is unknown. | Platinum Compounds such as carboplatin, oxaliplatin or satraplatin have been used as chemotherapy agents in CRPC in clinics. | [207,208,209] |
Double-Stranded Oligodeoxynucleotides decoys* | DNA sequences that are the same as GAS or ISRE elements and would bind to the STAT3 dimers in place of the actual sequence in the genome. | Not yet tested in PCa | [210,211] |
G-rich oligodeoxynucleotides (G quartets) | Very specific K+-dependent four-stranded DNA structures that occupy sites within the STAT3 SH2 domains. The selection method for these G quartets can effectively be used to block any interaction in the cell. | Supress growth in PCa cell lines through STAT3 inhibition. | [212,213] |
siRNA for STAT3 | Through formation of double stranded mRNA, siRNA can degrade mRNA for specific proteins using the DICER enzyme. | Repeatedly shown to reduce STAT3 activity in vitro and in vivo. | [214,215,216] |