Negative regulators of STAT3 signaling pathway in cancers

Figures & data

Figure 1 The negative regulators of JAK-STAT signaling. Binding of the ligand to cytokine receptor induces receptor dimerization and activation of receptor associated JAK kinase, which in turn phosphorylates STAT proteins. After forming a homodimer, STAT proteins translocate to the nucleus to control gene expression. Negative regulation of the JAK-STAT pathway is provided by PTPs, SOCS and PIAS proteins.

Figure 2 Structure characteristics of STATs, PIAS and SOCS. (A) Structure of STAT. ND, N domain; CCD, coiled coil domain; DBD, DNA-binding domain; LD, linker domain; SH2, Src homology 2 domain; TAD, transactivation domain. (B) The domain structure of PIAS proteins. SAP/LXXLL, SAF (scaffold attachment factor A and B) -A/B, Acinus and PIAS domain (it can recognize and bind to AT-rich DNA sequences), Within the SAP domain, there is a conserved LXXLL (it mediates interactions between nuclear receptors and their co-regulators) signature motif; PINIT, Pro-Ile-Asn-Ile-Thr motif (a highly conserved region of PIAS proteins and it may be involved in the nuclear retention of PIAS3); RLD, RING finger-like zinc binding domain; AD/SIM, acidic domain (AD), Within the AD, there is a putative SUMO1 interaction motif (SIM) in all PIASs except PIASy; S/T, serine-threonine rich region (in all PIASs except PIASy). (C) Structure of SOCS proteins. All eight members are characterized by their N-terminal region with variable length and limited homology, an extended SH2 domain (ESS), a central SH2 domain and a conserved SOCS box at the C-terminus.

Table 1 Direct inhibitors of STAT3

Molecules	Targets	Effects	Indications (clinical trial phase)	Refs
Peptide and peptidomimetics
PY*LKTK	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation151
ISS-610	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation152
SPI	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation153
CJ-1383	STAT3 SH2 domain	Inhibition of STAT3 phosphorylation	Not applicable	^Citation154
PM-73G	STAT3 SH2 domain	Inhibition of STAT3 phosphorylation	Not applicable	^Citation155
DBD-1	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation156
Non-peptide small molecules
Stattic	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation157
STA-21	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Psoriasis (phase I/II trial)	^Citation158
LLL-3	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation159
LLL-12	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation160
S3I-201	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation161
SF-1–066	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation162
SF-1–087	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation162
SF-1–121	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation162
S3I-1757	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation163
S3I-M2001	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation164
S3I-201.1066	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation165
BP-1–102	STAT3 SH2 domain	Inhibition of STAT3 dimerization	Not applicable	^Citation166
OPB-51,602	STAT3 SH2 domain	Inhibition of STAT3 phosphorylation	Advanced malignancies (phase I trial)	^Citation167, ^Citation168
CPA-1	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation169
CPA-7	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation169
Platinum(IV) tetrachloride	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation169
InS3−54	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation170
InS3−54A18	STAT3 DNA-binding domain	Inhibition of STAT3 DNA-binding	Not applicable	^Citation171

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