RJW100 (Figure 1), a synthetic ligand that contains the highly substituted hexahydropentalene core, was identified as a dual agonist of steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homolog-1 (LRH-1, NR5A2).¹ Both receptors belong to the nuclear receptor superfamily and have been shown to play crucial regulatory roles in human physiology. Therefore, small molecule modulators for LRH-1 and SF-1 are sought as medications for conditions such as inflammatory bowel disease, cancer, and metabolic diseases. Recent crystal structures of RJW100 with LRH-1 provided invaluable mechanistic data about its binding mode to this receptor.^2,3 However, the role of chirality in the activity of this racemic ligand is poorly understood. Herein, we unravel the binding specificity of the single RJW100 enantiomers: RR-RJW100 (Figure 1a) and SS-RJW100 (Figure 1b) with LRH-1 and SF-1 receptors.⁴ While both enantiomers displayed similar binding affinities, RR-RJW100 stabilized the receptors and was 46% more active than SS-RJW100 in LRH-1 luciferase reporter assays. With a new crystal structure, we discovered that SS-RJW100 adopted multiple configurations in the binding pocket, preventing a critical interaction required for receptor activation. Overall, these studies are the first to explore the role of chirality in activation of LRH-1 and SF-1 and provide a rationale for pursuing enantiomerically pure RJW100 and its derivatives in future drug design campaigns.

<b>Figure 1. </b>(R)-enantiomer (<b>a</b>) and (S)-enantiomer (<b>b</b>) of the dual agonist, RJW100.

Figure 1. (R)-enantiomer (a) and (S)-enantiomer (b) of the dual agonist, RJW100.

Eric Ortlund

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