First-in-class MTH1 inhibitors to exemplify the non-oncogene addiction concept for anticancer treatment
Oct 13,2014 03:43 | news
TH588 is a novel potent, selective cell permeable inhibitor of the nudix hydrolase family MTH1 protein with an IC50 of ~5 nM. Protein co-crystal structures demonstrate that TH588 binds in the active site of MTH1. It has excellent selectivity over other nudix family proteins and kinases present in the selectivity panel. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, the cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs. MTH1 inhibition by TH588 causes incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. TH588 is a good chemical tool to exemplify the non-oncogene addiction concept for anticancer treatment and validate MTH1 as a drug target.
In addition to TH588, there are two other MTH1 inhibitors available:
(S)-Crizotinib is a novel potent, selective and cell permeable MTH1 inhibitor with an IC50 of ~72 nM. It disrupts nucleotide pool homeostasis via MTH1 inhibition and induces an increase in DNA single-strand breaks in cancer cells. In vivo it can effectively suppress tumor growth in colon carcinoma xenograft model by once per day oral dosing. (R)-Crizotinib, which is (R)-enantiomer of the drug, is inactive against MTH1 in vitro. Loss-of-function of MTH1 impaired growth of KRAS tumor cells.
SCH51344 is a novel potent, selective and cell permeable MTH1 inhibitor with an IC50 of ~49 nM. It inhibits Ras-induced malignant transformation. It has no effect on Ras-induced ERK and JNK activation. SCH51344 inhibits Ras-induced membrane ruffling in REF-52 fibroblasts and blocks anchorage-independent growth of Ras-transformed tumor cell lines. It also induces DNA damage in SW480 colon cancer cells. Loss-of-function of MTH1 impaired growth of KRAS tumor cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344.
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