Intrinsically disordered proteins are potential drug targets

Abstract

Intrinsically disordered (ID) proteins that lack stable secondary and tertiary structure in substantial regions (or throughout) are prevalent in eukaryotes. They exist as ensembles of rapidly fluctuating structures and many undergo coupled folding and binding reactions. Because ID proteins are overrepresented in major disease pathways they are desirable targets for inhibition; however, the feasibility of targeting proteins without defined structures was unclear. Recently, small molecules have been found that bind to the disordered regions of c-Myc, Abeta, EWS-Fli1, and various peptides. As with structured targets, initial hits were further optimized to increase specificity and affinity. Given the number and biological importance of ID proteins, the ability to inhibit their interactions opens tremendous potential in chemical biology and drug discovery.

Figure 1

Prevalence of disordered regions in disease-associated proteins. Proteins associated with signaling and the indicated diseases show a much greater abundance of extended regions of disorder than eukaryotic proteins from Swiss-Prot and PDB (PDB_S25). Figure reproduced from reference [10].

Figure 2

Targeting Myc-Max dimerization: (a) cartoon of Myc-Max dimerization, binding of small molecules shifts the equilibrium to the left. (b) Small molecule inhibitors of Myc-Max dimerization from combinatorial and diversity libraries.

Figure 3

Additional Myc-Max dimerization inhibitors: (a) “credit-card” molecules, natural product, and Mycro series. (b) Known binding sites localized on the Myc bHLHZip; each binding site can be occupied independently and simultaneously.

Figure 4

Substrate targeted γ-secretase inhibitors and EWS-FLI1 binding molecule (YK-4-279.