Cryptochrome-2 (CRY2)

Cryptochrome-2 (CRY2) is a core component of the mammalian circadian clock, functioning as a transcriptional repressor within the transcription-translation negative feedback loop (TTFL) [1, 2]. It works alongside CRY1 and Period proteins to inhibit the activity of the CLOCK-BMAL1 heterodimer, thereby regulating the ~24-hour rhythms of physiological processes such as sleep, metabolism, and immune function [1, 15]. Beyond its role in timekeeping, CRY2 is a critical regulator of glucose and lipid metabolism, where it suppresses gluconeogenesis in the liver by inhibiting the expression of key enzymes like G6pc and Pck1 [1, 10]. In the context of disease, CRY2 dysfunction is linked to Type 2 diabetes, sleep phase disorders, mood disorders, and various cancers, including glioblastoma and osteosarcoma [1, 4, 8, 17]. Therapeutic strategies targeting CRY2 involve small-molecule stabilizers like SHP656 and KL001, which bind to the FAD-binding pocket to prevent proteasomal degradation, thereby lengthening the circadian period and improving metabolic homeostasis [1, 4, 6]. Recent developments have led to isoform-selective compounds like SHP1705, which has advanced to clinical trials for treating glioblastoma and metabolic conditions [1, 4].

Other names

Cryptochrome circadian regulator 2CRY2PHRE2

Stabilization of CRY2 protein to enhance transcriptional repression of CLOCK-BMAL1 and inhibit gluconeogenesis.