SAFit2 explained

SAFit2 is a drug which acts as a potent and selective inhibitor of the signalling factor FK506 binding protein 51 (FKBP51), which is involved in the downstream response to glucocorticoid release in the body.^[1] Since elevated glucocorticoid levels are a characteristic marker of chronic stress, blocking glucocorticoid signalling pathways using SAFit2 has been shown to counteract many of the associated symptoms such as obesity,^{[2] [3]} chronic pain,^{[4] [5]} depression and anxiety,^{[6] [7]} and addiction.^{[8] [9]} While SAFit2 itself is a relatively large molecule and is unlikely to have suitable properties to be developed for medical use, it has demonstrated that inhibition of FKBP51 may be a useful therapeutic approach for alleviating consequences of long-term chronic stress and pain.

See also

• Sirolimus
• Tacrolimus

Notes and References

1. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R, Binder EB, Almeida OF, Rühter G, Uhr M, Schmidt MV, Touma C, Bracher A, Hausch F . 6 . Selective inhibitors of the FK506-binding protein 51 by induced fit . Nature Chemical Biology . 11 . 1 . 33–7 . January 2015 . 25436518 . 10.1038/nchembio.1699 .
2. Balsevich G, Häusl AS, Meyer CW, Karamihalev S, Feng X, Pöhlmann ML, Dournes C, Uribe-Marino A, Santarelli S, Labermaier C, Hafner K, Mao T, Breitsamer M, Theodoropoulou M, Namendorf C, Uhr M, Paez-Pereda M, Winter G, Hausch F, Chen A, Tschöp MH, Rein T, Gassen NC, Schmidt MV . 6 . Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function . Nature Communications . 8 . 1 . 1725 . November 2017 . 29170369 . 10.1038/s41467-017-01783-y . 5700978 . 2017NatCo...8.1725B .
3. Häusl AS, Balsevich G, Gassen NC, Schmidt MV . Focus on FKBP51: A molecular link between stress and metabolic disorders . Molecular Metabolism . 29 . 170–181 . November 2019 . 31668388 . 10.1016/j.molmet.2019.09.003 . 6812026 .
4. Maiarù M, Tochiki KK, Cox MB, Annan LV, Bell CG, Feng X, Hausch F, Géranton SM . 6 . The stress regulator FKBP51 drives chronic pain by modulating spinal glucocorticoid signaling . Science Translational Medicine . 8 . 325 . 325ra19 . February 2016 . 26865567 . 10.1126/scitranslmed.aab3376 . 4880036 .
5. Maiarù M, Morgan OB, Mao T, Breitsamer M, Bamber H, Pöhlmann M, Schmidt MV, Winter G, Hausch F, Géranton SM . 6 . The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes . Pain . 159 . 7 . 1224–1234 . July 2018 . 29533388 . 10.1097/j.pain.0000000000001204 . 6012049 .
6. Hartmann J, Wagner KV, Gaali S, Kirschner A, Kozany C, Rühter G, Dedic N, Häusl AS, Hoeijmakers L, Westerholz S, Namendorf C, Gerlach T, Uhr M, Chen A, Deussing JM, Holsboer F, Hausch F, Schmidt MV . 6 . Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties . The Journal of Neuroscience . 35 . 24 . 9007–16 . June 2015 . 26085626 . 10.1523/JNEUROSCI.4024-14.2015 . 6605153 .
7. Pöhlmann ML, Häusl AS, Harbich D, Balsevich G, Engelhardt C, Feng X, Breitsamer M, Hausch F, Winter G, Schmidt MV . 6 . Pharmacological Modulation of the Psychiatric Risk Factor FKBP51 Alters Efficiency of Common Antidepressant Drugs . Frontiers in Behavioral Neuroscience . 2018 . 12 . 262 . 30483074 . 10.3389/fnbeh.2018.00262 . 6240676 . free .
8. König L, Kalinichenko LS, Huber SE, Voll AM, Bauder M, Kornhuber J, Hausch F, Müller CP . 6 . The selective FKBP51 inhibitor SAFit2 reduces alcohol consumption and reinstatement of conditioned alcohol effects in mice . Addiction Biology . 25 . 3 . e12758 . May 2020 . 31173432 . 10.1111/adb.12758 . 174811590 .
9. Savarese AM, Ozburn AR, Metten P, Schlumbohm JP, Hack WR, LeMoine K, Hunt H, Hausch F, Bauder M, Crabbe JC . 6 . Targeting the Glucocorticoid Receptor Reduces Binge-Like Drinking in High Drinking in the Dark (HDID-1) Mice . Alcoholism: Clinical and Experimental Research . March 2020 . 44 . 5 . 1025–1036 . 32154593 . 10.1111/acer.14318 . 7211124 .