Identifying druggable disease-modifying gene products

Abstract

Many disease genes encode proteins that are difficult to target directly using small molecule drugs. Improvements in libraries based on synthetic compounds, natural products, and other types of molecules may ultimately allow some challenging proteins to be successfully targeted; however, these developments alone are unlikely to be sufficient. A complementary strategy exploits the functional interconnectivity of intracellular networks to find druggable targets lying upstream, downstream, or in parallel to a disease-causing gene, where modulation can influence the disease process indirectly. These targets can be selected using prior knowledge of disease-associated pathways or identified using phenotypic chemical and genetic screens in model organisms and cells. These approaches should facilitate the identification of effective drug targets for many genetic disorders.

Figure 1

The druggable genome in relation to disease. a. Venn diagram illustrating the relationship between all potential human proteins, those proteins that are in principle druggable (green), those proteins encoded by disease genes (brown), and those proteins targeted by approved therapeutics (purple). The size of the ovals approximates the number of gene products in each category. While not considered here, it should be noted that one gene may give rise to multiple gene products through alternate splicing. b. Cartoon depicting disease gene products that are in principle undruggable, either because a suitable drug-binding fold is not present or because the disease-causing mutation eliminates protein production, and gene products that are druggable (e.g. accessible to a small molecule modulator). Small molecule modulators of druggable targets could in principle act to either impair the abnormal function of a target resulting from a gain of function mutation, or restore the impaired function of a target resulting from a partial loss of function mutation (not shown). Part (a) is in part adapted from Reference .

Figure 2

Chemical structures of small molecule compounds discussed in the text. a. Nutlin-3 directly inhibits the binding of p53 to Mdm-2. b. Z3 is a Janus kinase (Jak) inhibitor discovered through in silico screening. c. MLN4924 is a novel anti-cancer agent that selectively inhibits the NEDD8 activating enzyme (NAE). d. Erastin is an oncogenic Ras-selective lethal compound discovered through unbiased phenotypic screening. Erastin kills tumor cells through binding to the mitochondrial voltage-dependent anion channels 2 and 3. e. RSL3 is functionally similar to erastin but structurally distinct. The RSL3 target is unknown. f. Nimesulide is active in a zebrafish model of AML, counteracting the effects of the AML1-ETO oncogene on granulocytic blast cell differentiation.

Figure 3

Approaches to increase the size of the druggable genome, thereby facilitating both direct and indirect disease gene targeting. New chemical libraries, based on small molecule, fragment, or aptamer approaches may allow new protein folds or interaction interfaces to be targeted. In cases where these approaches fail, purely genetic approaches, involving the delivery of siRNAs directly to cells to silence mRNA expression may prove availing. RISC = RNAi-induced silencing complex, which binds and cleaves siRNA-mRNA double-stranded RNA duplexes.