FKBP inhibitors

Burkhard P, Hommell U, Sanner M, Walkinshaw MD. The discovery of steroids and other novel FKBP inhibitors using a molecular docking program. J Mol Biol 1999 287 853-8. 

Example of Scheme C Inhibition of Calcineurin by FKBP-Inhibitor Complexes... 

Figure 6.17 Cartoon depicting the interactions of FKBP with inhibitor and the subsequent binding of the FKBP Inhibitor binary complex to the enzyme calcineurin (E).

Zhao et al. implemented a structure-based docking protocol to narrow down 500 compounds from a database of 57 compounds in their pursuit of FKBPs inhibitors (89). A novel scaffold was designed using the information obtained from the binding mode analysis of a known weak binder. To avoid any scoring function shortcomings, three scoring functions were used to select the 500 compounds. Of these, 43 were synthesized and tested to identify one potent inhibitor in a mouse peripheral synthetic nerve model. 

The Discovery of Steroids and Other Novel FKBP Inhibitors Using a Molecular Docking Program. 

Knowledge of these processes has been facilitated by studying in vivo effects of nonimmunosuppressive FKBP inhibitors such as GPI1046, JNJ460, V10,367, GPI1048, and GPI1485, to name the most prominent compounds. 

Fig. 12.11 Some examples of cyclic FKBP inhibitors that exhibit neurotrophic activity.

The 3,4,5-trimethoxyphenyl group is also an excellent replacement for the pyran moiety of FK506, as reported by workers at Vertex Pharmaceuticals.189 Compound 7 is a very potent FKBP inhibitor, and the branched ester semaphore compound 8 is equipotent with FK506 as an FKBP 12 inhibitor and ligand. Replacement of the pipecolic acid ring... 

Addition of the L-732,531 FKBP binary complex to a calcineurin activity assay resulted in increasingly nonlinear progress curves with increasing binary complex concentration. The htting of the data to Equation (6.3) revealed an inhibitor concentration effect on v-, as well as on vs and obs, consistent with a two-step mechanism of inhibition as in scheme C of Figure 6.3. Salowe and Hermes analyzed the concentration-response effects of the binary complex on v, and determined an IC50 of 0.90 pM that, after correction for I.S I/A (assuming competitive inhibition), yielded a A) value for the inhibitor encounter complex of 625 nM. 

AGb. We successfully applied this expression to correlate observed binding affinities for series of inhibitors with thrombin,18 HTV-RT,28 and FKBP.20... 

With another immunophilin, FK binding protein (FKBP), experiments were performed using isotope editing of the [U-13C]-labeled inhibitor ascomycin (bound to unlabeled FKBP) [34], as well as by isotope filtering with unlabeled ascomycin derivatives (bound to labeled FKBP) [35],... 

FK506 is the propriety name given to an immunosuppressant by a Japanese company. FK506 is a macrolide antibiotic, isolated from streptomyces tsukubaensis. It is a potent inhibitor of T cell activation, preventing allograft rejection. FK506 binds to FK-binding proteins, the FKBP s. 

Sirohmus is a macrocychc lactone produced by the bacteria Streptomyces hygroscopious. Like the calcineurin inhibitors cyclosporine and tacrolimus its mechanism of action involves formation of a complex with an immunophiUn, in this case, FKBP-12. Unlike cyclosporine and tacrolimus, sirohmus does not affect calcineurin activity but binds to and inhibits the mammalian kinase, target of rapamycin (mTOR.). mTOR is a key enzyme in cell-cycle progression. When inhibited this kinase blocks cell cycle progression at the G1 to S phase transition (Dumont and Su, 1996 Sehgal, 2003). 

Figure 1.23 SMase inhibitors (42) and FKBP 12 rotamase inhibitors (43). Numbers within the parentheses are IC50 values.

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