TABLE 1.

SphK1 inhibitors and potential functions.

Classification	Inhibitors	Targeted molecules	Dosage	Effects	Potential mechanisms	Characteristic	References
SphK1 selective inhibitors (Sphingosine Analogues)	SK1-I (BML258)	SphK1	Ki = 10 μM	S1P levels↓, cell apoptosis↑, inflammation↓, autophagy↑	Increases the expression of ceramide derivatives, decreased S1P level, mediate ERK1/2 and Akt signal, increased the transcriptional activity of tumor suppressor protein TP53	No activity at PKCα, PKCδ, PKA, AKT1, ERK1, EGFR, CDK2, IKKβ or CamK2β; high solubility and delivery in vivo	Paugh et al. (2008); Pitman and Pitson (2010); Nagahashi et al. (2012); Lima et al. (2018); Chahar et al. (2021)
			0–20 μM
			75 mg/kg
	LCL351/146	SphK1	Ki = 5 μM, 50 μM	S1P levels↓, pro-inflammatory cytokine↓, no effect on cell death and cell cycle, neutrophil infiltration and immune responses↓	induced SphK1 degradation	Two erythro diastereoisomers; a novel therapeutic target for IBD	Sharma (2011); Pulkoski-Gross et al. (2017)
	6ag/9ab/12aa	SphK1	IC50 = 0.65, 0.05, 0.062 μM	—	—	Significantly more potent than the previously reported SphK1 inhibitor N, N-dimethylsphingosine; 3-hydroxyproline improves the activity and ADME characteristics in vitro	Xiang et al. (2009)
(Amidine Inhibitors)	VPC96091	SphK1	Ki = 0.1, 1.5 μM	S1P levels↓	Increased Akt/ERK phosphorylation	An effective selective SphK1 inhibitor, reduced the S1P level of human leukemia U937 cells and mice	Foss et al. (2009); Kharel et al. (2011); University of Virginia Patent Foundation (2014); Kotthaus et al. (2011)
	SLP 7111228	SphK1	Ki = 48 nM	S1P levels↓	—	An effective selective inhibitor of SphK1; engagement of the target is indexed by blood S1P levels	Kharel et al. (2012); Patwardhan et al. (2015)
	Compound 28	SphK1	Ki = 0.3 μM, 6 μM	S1P levels↓	initiate growth arrest	No activity at DAG (γ, δ1, ζ), PKC α	Mathews et al. (2010)
(Piperidine Analogue)	Compound 82	SphK1	IC50 = 0.02, 0.1 μM	S1P levels↓, good mean residence time, and bioavailability of 32%	Hydrogen bonds are formed by the aminoalcohol portion of compound 82 and two key residues of aspartate in SphK1	Competitively inhibits SphK1; no activity at anti-tumor	Gustin et al. (2013); Wang et al. (2013); Rex et al. (2013)
	RB-005	SphK1	IC50 = 3.6 μM	The inhibition of ceramide synthase	Degradation of SphK1 proteasome↑	Derivative obtained from the route of synthesizing FTY-720; therapeutic potential for proliferative diseases, including PAH; potential inhibition of ceramide synthase	Baek et al. (2013a); Baek et al. (2013b); MacRitchie et al. (2016)
	Compound1/2/3	SphK1	IC50 = 1–1,000 nM	—	—	A series of selective inhibitors of SphK1; Therapeutic potential for RA and cancer	Frank (2013); Lynch et al. (2016)
(Pyrrolidine Analogue)	PF-543	SphK1	IC50 = 2 nM; Ki = 3.6 nM; 10–1,000 nM; 1 mg/kg	apoptosis↑, necrosis↑, and autophagy↑, S1P levels↓, Sph↑, no effect on the level of ceramide, inflammation↓	Degradation of SphK1 proteasome↑; inhibition of neutrophil infiltration and inflammatory cytokine release	A potent, selective, reversible and Sph-competitive SphK1 inhibitor; inhibitor was bound in the SphK1 substrate pocket with a J-shaped structure	Schnute et al. (2012); Byun et al. (2013); Wang et al. (2014b); Ha et al. (2020); Kim et al. (2020); Liu and Jiang (2020); Zhong et al. (2020); Chen et al. (2021b); Deng et al. (2021)
	CHJ01	SphK1	IC50 = 8.89 μM	S1P levels↓, Cer levels↑	Decrease of inflammatory cytokines in RA rat model	Effective treatment of RA in vivo and in vitro	Kuroda et al. (2002); Salma et al. (2009); Chen et al. (2021a)
	Compound 51	SphK1	IC50 = 0.058 μM	Modest oral bioavailability, qualified half-life in blood circulation	—	Better metabolic stability than PF-543	Xiang et al. (2010)
Dual SphK1/2 inhibitor (Non-Lipid Small Molecules)	SKI-I	SphK1, SphK2, ERK2, PKC, PI3K	IC50 = 1.2 μM	S1P levels↓, Cer levels↑, apoptosis↑, autophagy↑	—	a competitive Sph inhibitor of SphK1 and SphK2; anti-tumor activity	French et al. (2003); French et al. (2006); Hengst et al. (2010); Young et al. (2012)
	SKI-Ⅱ (SKi)	SphK1/2	Ki = 16, 8 μM	S1P levels↓, Ceride and Sph levels↑, apoptosis ↓, proliferation and migration↓, inflammation↓, oxidative stress↓	Triggering iysosomal degradation of SphK1; inhibit the activity of Des1; destroying the negative regulator Keap1	Oral bioavailable properties; the prevention of oxidative stress	French et al. (2003); Loveridge et al. (2010); Ren et al., 2010; Cingolani et al. (2014); Noack et al. (2014); Yang et al. (2015); Aurelio et al. (2016); Bien-Möller et al. (2016); McNaughton et al. (2016); Sun and Wang (2021)
	MP-A08	SphK1/2	Ki = 27, 7 μM	S1P levels↓, Cer and Sph levels↑, apoptotic↑, proliferation↓, tumor angiogenesis↓	No effects on proteasome degradation; target the ATP binding pocket of SphK1	An ATP competitive dual SphK1/2 inhibitor; higher affinity for SphK2; overcomes off-target effects	Cingolani et al. (2014); Pitman et al. (2015)
	DHS (Safingol)	SphK1, SphK2, PKC-α	Ki = 3–6 μM	Anticancer activity, apoptosis↑	—	A SphK1 competitive inhibitor; the first SphKs inhibitor to enter clinical trials as an anticancer agent	Schwartz et al. (1997); Coward et al. (2009); Dickson et al. (2011)
(Lipid Small Molecules)	DMS	SphK1, SphK2, PKC, CERK	Ki = 16 μM	Anticancer activity, apoptosis↑, hemolysis↑	—	The first direct SphKs inhibitor	Sweeney et al. (1996); Yatomi et al. (1996); Edsall et al. (1998); Sah et al. (2021)
Other SphK1 inhibitors	SKI-178	SphK1/2	Ki = 1.33 μM	apoptotic↑, cell death↑, anti-cancer↑	—	ATP non-competitively and selectively inhibits	Dick et al. (2015); Hengst et al. (2017); Hengst et al. (2020b)
	SK-F	SphK1	Ki = 1 μM 5 mg/kg	Cell growth↓, viability↓, anti-tumor↑	—	A selective and competitive SphK1 inhibitor; no significant systemic toxicity in the treatment of mouse breast tumors	Alshaker et al. (2018)
	SLC 4011540	SphK1/2	Ki = 120 nM, 90 nM	S1P levels↓, Sph remained unchanged	—	SphK1/2 dual inhibitor; characteristic feature is the presence of an electron-deficient phenyl ring	Childress et al. (2017)
	B-5354C/F-12509a	SphK1; SphK1/2	Ki = 18; 12 μM	S1P levels↓, Cer and Sph levels↑, cell death↓	—	Isolated by extraction from a discomycete, Trichopezizella barbata and a novel marine bacterium; non-competitive inhibitor	Bonhoure et al. (2006); Cuvillier (2008)
	11b	SphK1	IC50 = 3.1 μM	—	—	A hydrophobic moiety with naphthalene ring substituent; interaction with asp178	Gustin et al. (2013); Vettorazzi et al. (2020)
	Balanocar-pol	SphK1	Ki = 160 ± 40 μM	Cell apoptosis↑, proliferation↓	Changes in the SphK1 protein turnover	Sph-competitive inhibitor	Nakagawa et al. (2001); Sahidin et al. (2005); Loveridge et al. (2010); Lim et al. (2012)