Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice

Nat Commun. 2022 Nov 8;13(1):6742. doi: 10.1038/s41467-022-34582-1.

Seref Gul ¹ ², Yasemin Kubra Akyel ³ ⁴, Zeynep Melis Gul ⁵, Safak Isin ⁵, Onur Ozcan ⁵, Tuba Korkmaz ⁶, Saba Selvi ⁶, Ibrahim Danis ⁷ ⁸, Ozgecan Savlug Ipek ⁹ ¹⁰, Fatih Aygenli ⁶, Ali Cihan Taskin ¹¹, Büşra Aytül Akarlar ⁵, Nurhan Ozlu ⁵, Nuri Ozturk ⁶, Narin Ozturk ³, Durişehvar Özer Ünal ⁷ ⁸, Mustafa Guzel ⁹ ¹², Metin Turkay ¹³, Alper Okyar ³, Ibrahim Halil Kavakli ¹⁴ ¹⁵

Affiliations

1 Department of Chemical and Biological Engineering, Koc University, 34450, Sariyer-Istanbul, Turkey.
2 Department of Biology, Biotechnology Division, İstanbul University, TR-34116, Beyazit-Istanbul, Turkey.
3 Faculty of Pharmacy, Department of Pharmacology, İstanbul University, TR-34116, Beyazit-Istanbul, Turkey.
4 School of Medicine, Department of Medical Pharmacology, Istanbul Medipol University, Istanbul, Turkey.
5 Department of Molecular Biology and Genetics, Koc University, İstanbul, Turkey.
6 Department of Molecular Biology and Genetics, Gebze Technical University, Gebze, 41400, Kocaeli, Turkey.
7 Faculty of Pharmacy, Department of Analytical Chemistry, İstanbul University, TR-34116, Beyazit-Istanbul, Turkey.
8 İstanbul University Drug Research and Application Center (ILAM), TR-34116, Beyazıt-Istanbul, Turkey.
9 Regenerative and Restorative Medicine Research Center (REMER), İstanbul Medipol University, Kavacik Campus, Kavacik-Beykoz/Istanbul, 34810, Turkey.
10 Department of Chemistry, Graduate School of Natural and Applied Sciences, Yildiz Technical University, Besiktas/Istanbul, 34349, Turkey.
11 Animal Research Facility, Research Center for Translational Medicine, Koc University, Rumelifeneri yolu, 34450, Sariyer-Istanbul, Turkey.
12 International School of Medicine, Department of Medical Pharmacology, Kavacik Campus, İstanbul Medipol University, Kavacik-Beykoz/Istanbul, 34810, Turkey.
13 Department of Industrial Engineering, Koc University, Istanbul, Turkey.
14 Department of Chemical and Biological Engineering, Koc University, 34450, Sariyer-Istanbul, Turkey. hkavakli@ku.edu.tr.
15 Department of Molecular Biology and Genetics, Koc University, İstanbul, Turkey. hkavakli@ku.edu.tr.

PMID: 36347873 DOI: 10.1038/s41467-022-34582-1

Abstract

Cryptochromes are negative transcriptional regulators of the circadian clock in mammals. It is not clear how reducing the level of endogenous CRY1 in mammals will affect circadian rhythm and the relation of such a decrease with Apoptosis. Here, we discovered a molecule (M47) that destabilizes Cryptochrome 1 (CRY1) both in vitro and in vivo. The M47 selectively enhanced the degradation rate of CRY1 by increasing its ubiquitination and resulted in increasing the circadian period length of U2OS Bmal1-dLuc cells. In addition, subcellular fractionation studies from mice liver indicated that M47 increased degradation of the CRY1 in the nucleus. Furthermore, M47-mediated CRY1 reduction enhanced oxaliplatin-induced Apoptosis in Ras-transformed p53 null fibroblast cells. Systemic repetitive administration of M47 increased the median lifespan of p53^-/- mice by ~25%. Collectively our data suggest that M47 is a promising molecule to treat forms of Cancer depending on the p53 mutation.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-148764

M47

99.90%, Apotosis Inducer

Apoptosis

Cancer

Name
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