A total of 48 genes encoding NRs in the human genome were characterized in our current study (Figure 1A and Data set 1). Among them, 37.5% (18/48) were defined as understudied genes (i.e., score<150) based on their PubTator scores, which represent the numbers of publications related to that given gene. Published studies on NRs were narrowly focused on limited subfamilies such as subfamilies 1 and 3. Among NRs with higher PubTator scores, 10.4% (5/48) showed extremely high scores (> 4,000), representing the most pervasively studied NRs including ESR1, AR and PGR. In contrast, NRs in subfamily 2 were commonly understudied (83.3%), including 75.0% with PubTator scores less than 100. Next, the drug development status of NRs was analyzed based on their target development levels (TDLs), which were estimated by the Illuminating the Druggable Genome (IDG) project of NIH. As expected, NRs showed significantly higher portions of Tclin (37.5%, i.e., targeted by approved drugs) and Tchem (39.6%, i.e., targeted by small molecules that satisfy the activity thresholds; Figure 1A, 1B), compared to all protein-coding genes in the human genome (2.9% Tclin and 5.9% Tchem). At the level of subfamilies, subfamilies 1 and 3 were enriched with NRs that were defined as Tclin or Tchem. Subfamily 3, which included ESR1, AR and PGR, had the highest percentage of members with approved drugs (Tclin: 66.7%; Figure 1C). In contrast, other subfamilies showed lower TDLs, and subfamilies 0, 4, 5 and 6 had no members classified as Tclin. Consistently, the numbers of chemical compounds/approved drugs were highly correlated with the PubTator scores across NRs. Although NRs represent one of the most well-established druggable gene families, showing significantly higher level of TDLs (Tclin and Tchem) compared to protein-coding genes and other druggable gene families overall, the distribution of targeted NRs was extremely biased among sub-families, and was even unbalanced within the same subfamily (Figure 1C). For example, 75.3% (162/215) of approved NR drugs target the NRs in subfamily 3, and 63 of them target a single member of this subfamily (glucocorticoid receptor, NR3C1). Finally, the application of NR drugs is limited in cancer therapy. Although 7 NRs currently serve as potential anti-cancer drug targets under clinical development, the approved applications of NR-targeting drugs in oncology were limited to ER, AR, RXRs and RARs. Taken together, given their promising druggable features, the NR superfamily provides large and unexplored opportunities for further development of anti-cancer drugs.
