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Targeting cancer using KAT inhibitors to mimic lethal knockouts.

Forskningsöversiktsartikel
Författare James A L Brown
Emer Bourke
Leif A Eriksson
Michael J Kerin
Publicerad i Biochemical Society transactions
Volym 44
Nummer/häfte 4
Sidor 979-86
ISSN 1470-8752
Publiceringsår 2016
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 979-86
Språk en
Länkar dx.doi.org/10.1042/BST20160081
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord acetyltransferase, anacardic acid, bisubstrate, breast cancer, curcumin, garcinol, HAT, histone, HTATIP, inhibitor, KAT, Kat5, Lys-CoA, lysine, MG-149, NU9056, pentamidine, TH1834, Tip60.
Ämneskategorier Läkemedelskemi, Cell- och molekylärbiologi, Teoretisk kemi

Sammanfattning

Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.

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