Structure-based design of novel calcineurin (PP2B) inhibitors
The design, synthesis and evaluation of small molecule inhibitors of human calcineurin is described. These ligands were derived from the known nonspecific phosphatase inhibitor endothall, and were modified to enhance binding and selectivity toward calcineurin using protein crystal structure information.
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Cited by (38)
Cantharidin analogue alleviates dextran sulfate sodium-induced colitis in mice by inhibiting the activation of NF-κB signaling
2023, European Journal of Medicinal ChemistrySynthesis of cytotoxic spirocyclic imides from a biomass-derived oxanorbornene
2021, TetrahedronCitation Excerpt :Its synthesis is readily achieved through the Diels-Alder [4 + 2] cycloaddition between furan and maleic anhydride, followed by subsequent reduction of the alkene [18]. This has led to numerous investigations into synthetic analogues of cantharidin 5, with several groups reporting structure-activity relationships (SAR) for cytotoxicity and PP1/PP2A inhibition following modification of the 7-oxabicylo[2.2.1]heptyl ring system [19–23] or ring-opening the anhydride [24–29]. However, these synthetic analogues have seldom shown cytotoxicity comparable to cantharidin 5, suggesting only limited modification of the parent compound is tolerated.
Norcantharimide analogues possessing terminal phosphate esters and their anti-cancer activity
2011, Bioorganic and Medicinal ChemistryCitation Excerpt :Norcantharidin is reported to induce apoptosis in human cervical,13,14 oral,15,16 melanoma,17 ginival,15 bladder,18 adenocystic carcinoma,19 glioblastoma,20 bone,21 leukaemia,21 ovarian,22 liver,23,24,21 gall bladder25 and colon26–29 cancer cell lines, however so far the main application is for hepatoma.30,31 Numerous research groups have reported various structural modifications of norcantharidin, ones in which protein phosphatase inhibition is maintained and others in which this activity is removed, but anti-proliferative activity is maintained.2–4,29,31–43 As is routine in our laboratory we conducted both protein phosphatase 1 and 2A inhibition studies, and in keeping with our earlier reports relating to similar cantharimides, all analogues herein were devoid of any protein phosphatase inhibitory properties.
Synthesis and biological activity of Δ-5,6-norcantharimides: importance of the 5,6-bridge
2010, European Journal of Medicinal ChemistryCitation Excerpt :However through a series of modified literature procedures we gained access to the desired analogues (see Supplementary Material) [27–37]. With access to anhydrides 3–6, we were also keen to explore the SAR along similar lines to our prior evaluations with cantharidin and norcantharidin [16–25]. We thus investigated the development of small focused libraries of imides generated by treatment of anhydride 3–6 with a small library of amines (Scheme 1: Library A, amines a–f; Library B, amines g–l; Library C, amines m–p).
Interaction of calcineurin with its activator, chlorogenic acid revealed by spectroscopic methods
2009, BiochimieCitation Excerpt :A number of other natural compounds such as FR901459 [5], polyunsaturated lipids [6], and retinoic acid [7], have inhibitory activity against CN. The second category consists of synthetic inhibitors, mainly metal ion chelates such as PD144795 and endothal derivatives [8,9]. Inhibitors of the third category are endogenous cellular proteins and may act in vivo as regulators of CN's function; examples are the 79 kDa protein kinase A anchoring protein AKAP79 [10], calcineurin binding protein-cain/cain1 [11] and the calcineurin regulator-RCN/MCIP/CBP1 [12].