SHP1705 is the first circadian clock-modulating compound found safe and well-tolerated in Phase I clinical trials.
SHP1705 shows increased selectivity for the CRY2 isoform and greater potency against glioblastoma stem cell (GSC) viability compared to earlier .
In mice with GBM tumors derived from , SHP1705 prolonged survival.
The combination of SHP1705 with the REV-ERB agonist SR29065 exhibited synergistic effects against multiple GSC lines and differentiated GSCs.
The findings suggest that targeting circadian clock components may be a viable strategy for addressing chemoradiation resistance in GBM.
Simplified
BACKGROUND: It has been reported that circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), are essential for glioblastoma (GBM) stem cell (GSC) biology and survival. Consequently, we developed a novel Cryptochrome (CRY) activator SHP1705, which inhibits BMAL1-CLOCK transcriptional activity.
METHODS: We utilized GlioVis to determine which circadian genes are differentially expressed in non-tumor versus GBM tissues. We employed in vitro and in vivo methods to test the efficacy of SHP1705 against patient-derived and xenografts in comparison to earlier CRY activator scaffolds. We applied a novel REV-ERB agonist SR29065, which inhibits BMAL1 transcription, to determine whether targeting both negative limbs of the circadian transcription-translation feedback loop (TTFL) would yield synergistic effects against various GBM cells.
RESULTS: SHP1705 is the first circadian clock-modulating compound to be found safe and well-tolerated in Phase I clinical trials. SHP1705 has increased selectivity for the CRY2 isoform and potency against GSC viability compared to previously published , making it promising for applications in GBM where CRY2 levels are found to be low. SHP1705 prolonged survival in mice bearing GBM tumors established with GSCs. When combined with novel REV-ERB agonist SR29065, SHP1705 displayed synergy against multiple GSC lines and differentiated GSCs (DGCs).
CONCLUSIONS: We demonstrate the efficacy of SHP1705 against GSCs, which pose as a major source of chemoradiation resistance leading to poor GBM patient prognosis. Novel circadian clock compounds have high potential for targeting GBM as single agents or in combination with each other or current standard-of-care.
Key numbers
42
Subjects Treated
Subjects receiving single oral doses of SHP1705 in Phase I trial.
30 mg/kg
Increased Survival
Dosage of SHP1705 administered to mice showing prolonged survival.
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