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Validation and development of MTH1 inhibitors for treatment of cancer

Artikel i vetenskaplig tidskrift
Författare U. W. Berglund
K. Sanjiv
H. Gad
C. Kalderen
T. Koolmeister
T. Pham
C. Gokturk
R. Jafari
G. Maddalo
B. Seashore-Ludlow
A. Chernobrovkin
A. Manoilov
I. S. Pateras
A. Rasti
A. S. Jemth
I. Almlof
O. Loseva
T. Visnes
Berglind Osk Einarsdottir
F. Z. Gaugaz
A. Saleh
B. Platzack
O. A. Wallner
K. S. A. Vallin
M. Henriksson
P. Wakchaure
S. Borhade
P. Herr
Y. Kallberg
P. Baranczewski
E. J. Homan
E. Wiita
V. Nagpal
T. Meijer
N. Schipper
S. G. Rudd
L. Brautigam
A. Lindqvist
A. Filppula
T. C. Lee
P. Artursson
Jonas A Nilsson
V. G. Gorgoulis
J. Lehtio
R. A. Zubarev
M. Scobie
T. Helleday
Publicerad i Annals of Oncology
Volym 27
Nummer/häfte 12
Sidor 2275-2283
ISSN 0923-7534
Publiceringsår 2016
Publicerad vid Institutionen för kliniska vetenskaper, sektionen för kirurgi och kirurgisk gastroforskning, Avdelningen för kirurgi
Sahlgrenska Cancer Center
Sidor 2275-2283
Språk English
Länkar dx.doi.org/10.1093/annonc/mdw429
Ämnesord MTH1, reactive oxygen species, cancer, small molecule inhibitors, DNA damage, cell survival, target, mutations, reveals, disease, protein, potent, pool, Oncology
Ämneskategorier Cancer och onkologi

Sammanfattning

Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

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