HDAC Inhibitors as Epigenetic Regulators

For S1P1 receptor signaling, CYM-5442 or SEW2871, both potent selective S1P1 agonists, and W146, a selective S1P1 antagonist, should be sufficient to elucidate S1P1 receptor involvement. A431 cells38. Ironically, these chemicals turned out to be selective or non-selective agonists of cloned LPA receptors (see details below). In the early era of LPA biology, suramin and lysophosphatidylglycerol were used to demonstrate GPCR involvement in LPA responses46 and as an antagonist of LPA-induced Ca2+ responses in Jurkat T cells47, respectively. LPA GPCR agonists Since the discovery of the three-Edg family of LPA receptors, the development of selective receptor-subtype agonists and antagonists has accelerated. The optimal chain length and the presence of double bonds have been found to vary depending on receptor subtype. For example, LPA3 showed a preference for unsaturated LPA similar to oleoyl LPA48, whereas LPA6 showed a preference for 2-acyl LPA19. Synthesis of LPA derivatives with phosphonate or thiophosphate groups instead of the phosphate group showed receptor-subtype selective Sntb1 activity similar to 1-oleoyl-2-configuration of S1P was demonstrated using the cloned receptors77. The linkage of the immune modulator FTY720 to S1P receptors, however, boosted this area of research and opened a new direction for S1P biology78, 79, 80. Lymphopenia induction by inhibiting lymphocyte egress from lymphoid organs was shown to be mediated through the S1P1 receptor81. High-throughput screening (HTS) of an available chemical library showed that SEW2871 acted as an active heterocyclic S1P1 selective agonist81, 82 and compound 26 was synthesized as a potent 3,5-diphenyl-12,4-oxadiazole S1P1 agonist83. Later, using ultra-HTS, 3,5-diaryloxadiaxole (CYM5181) and dicyclohexylamide were found to be selective agonists for S1P1 and S1P3, respectively84. Using computational modeling, CYM-5442 was developed as an S1P1 selective agonist that was Beta-Lapachone more potent than CYM518185. AUY954, an aminocarboxylate analogue of FTY720, was also introduced as an S1P1 selective agonist86. “type”:”entrez-protein”,”attrs”:”text”:”VPC01091″,”term_id”:”1657354296″VPC01091, a cyclized analogue of FTY720, was shown to act as an orally active S1P1 agonist and an S1P3 antagonist87. KRP-203 is a pro-drug immune modulator similar to FTY720; the phosphorylated form of KRP-203 was shown to be a selective S1P1 agonist88, 89. Constrained azacyclic analogues of FTY720 showed selective agonist activities on S1P4 and S1P5 receptors90. Finally, phytosphingosine-1-phosphate was shown to act as a potent and selective agonist on the S1P4 receptor76. S1P GPCR antagonists Suramin Beta-Lapachone was temporarily used as an S1P3 antagonist75, 91. Human S1P5 was also reported to be sensitive to suramin and its analogue NF02392. Following screening of an available chemical library, JTE-013, a pyrazopyridine derivative, was identified as an S1P2 antagonist93, 94. Modification of the FTY720-phosphate structure led to the development of “type”:”entrez-protein”,”attrs”:”text”:”VPC23019″,”term_id”:”1643589982″VPC23019 and “type”:”entrez-protein”,”attrs”:”text”:”VPC25239″,”term_id”:”1668388349″VPC25239 as selective S1P1/S1P3 antagonists95. As mentioned above, “type”:”entrez-protein”,”attrs”:”text”:”VPC01091″,”term_id”:”1657354296″VPC01091 is an orally active S1P1 agonist and S1P3 antagonist87. W146, hexyl phenyl amide phosphonate, was found to be a selective S1P1 antagonist96. “type”:”entrez-protein”,”attrs”:”text”:”VPC44116″,”term_id”:”1641881428″VPC44116, an octyl analogue of W146 and -aminophosphonate analogue of “type”:”entrez-protein”,”attrs”:”text”:”VPC23019″,”term_id”:”1643589982″VPC23019, antagonized lymphopenia and lung permeability via the S1P1 receptor97. SB64146 was reported to act as an inverse agonist on the S1P1 receptor98. Ascotricins A and B were isolated from a cultured broth Beta-Lapachone of a fungus identified as and shown to Beta-Lapachone inhibit the S1P1 receptor and S1P-mediated HUVEC migration99. Sankyo Co synthesized compound lead 2 (CL2), 2-(4-ethoxyphenoxy)-5-(3-octadecyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonate, which antagonized the S1P1 S1P3 S1P2 receptors100. Human S1P1 receptor-selective antagonist and agonist effects of a rat monoclonal antibody (4B5.2) were also reported101. Using a 3D database search, BML-241, 2-alkylthiazolidine-4-carboxylic acid, was found to act as an S1P3 antagonist, but its selectivity and potency were not recapitulated in CHO-K1 cells expressing the S1P3 receptor102, 103. A pharmacophore-based design of an S1P3 antagonist with a 3,4-dialkyoxybenzophenone scaffold was suggested104. Pharmacological tools for S1P GPCR signaling Commercially available tools for studying S1P receptor subtypes are highlighted in Figure 2. For S1P1 receptor signaling, CYM-5442 or SEW2871, both potent selective S1P1 agonists, and W146, a selective S1P1 antagonist, should be sufficient to elucidate S1P1 receptor involvement. S1P2 receptor signaling could be dissected using JTE-013, an S1P2 selective antagonist. For S1P3 GPCR signaling, a combined application of an S1P1,3 antagonist (“type”:”entrez-protein”,”attrs”:”text”:”VPC23019″,”term_id”:”1643589982″VPC23019) and S1P1 antagonist (W146) or S1P1 agonist (CYM-5442) could be useful. Phytosphingosine 1-phosphate, an S1P4 selective agonist, could be used to study S1P4-mediated signaling. S1P1,3 antagonist (“type”:”entrez-protein”,”attrs”:”text”:”VPC23019″,”term_id”:”1643589982″VPC23019)-insensitive, S1P2 antagonist (JTE-013)-insensitive, S1P4 agonist-non-responsive, and S1P- or FTY720-phosphate-sensitive signaling might be interpreted as S1P5 receptor or unidentified S1P receptor signaling (Table 2). Open in a separate window Figure 2 Structures of.