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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.
 
 
How to order: Xcess Biosciences, a premier reagent and service company, provides compounds in 10 mM DMSO solution and up to grams solid form. Please visit our website for order information, and other innovative products. Especially Xcess Biosciences continues to add more novel small molecule chemical probes to our Epigenetic Modulator Tool Box (right now we offer 74 unique compounds) andUbiquitin Modulator Tool Box (right now we offer 16 unique compounds).  Some newly add-in compounds are:
  • A-366 - a novel highly potent, selective and cell permeable G9a/GLP histone lysine methyltransferase inhibitor with an IC50 ~3.3 nM.
  • GPR39-C3 - the first potent, selective and orally bioavailable GPR39 agonist.
  • WAY-316606 is a novel potent and selective inhibitor of secreted frizzled-related protein-1 (sFRP-1) to increase Wnt signaling.
 
 
Reference:
  1. Gad H, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool. (2014) Nature. 508(7495):215-21.
  2. Huber KV, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. (2014) Nature. 508(7495):222-7.
  3. Kumar CC, et al. SCH 51344 inhibits ras transformation by a novel mechanism. (1995) Cancer Res. 55, 5106–5117.
  4. Walsh AB, et al. SCH 51344-induced reversal of RAS-transformation is accompanied by the specific inhibition of the RAS and RAC-dependent cell morphology pathway. (1997) Oncogene. 15(21):2553-60.
  5. Kumar CC, et al. SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway. (1999) Ann N Y Acad Sci. 886:122-31.