sch-51344 and Colonic-Neoplasms

sch-51344 has been researched along with Colonic-Neoplasms* in 1 studies

Other Studies

1 other study(ies) available for sch-51344 and Colonic-Neoplasms

ArticleYear
Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy.
    Nature, 2014, Apr-10, Volume: 508, Issue:7495

    Activated RAS GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small molecules, such as SCH51344, but their molecular mechanism of action remains generally unknown. Here, using a chemical proteomic approach, we identify the target of SCH51344 as the human mutT homologue MTH1 (also known as NUDT1), a nucleotide pool sanitizing enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells, whereas MTH1 overexpression mitigated sensitivity towards SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 activity. Surprisingly, the clinically used (R)-enantiomer of the drug was inactive, whereas the (S)-enantiomer selectively inhibited MTH1 catalytic activity. Enzymatic assays, chemical proteomic profiling, kinome-wide activity surveys and MTH1 co-crystal structures of both enantiomers provide a rationale for this remarkable stereospecificity. Disruption of nucleotide pool homeostasis via MTH1 inhibition by (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models. Our results propose (S)-crizotinib as an attractive chemical entity for further pre-clinical evaluation, and small-molecule inhibitors of MTH1 in general as a promising novel class of anticancer agents.

    Topics: Aminoquinolines; Animals; Antineoplastic Agents; Colonic Neoplasms; Crizotinib; Crystallization; Disease Models, Animal; DNA Breaks, Single-Stranded; DNA Repair; DNA Repair Enzymes; Female; Homeostasis; Humans; Mice; Mice, SCID; Models, Molecular; Nucleotides; Phosphoric Monoester Hydrolases; Protein Conformation; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyridines; ras Proteins; Substrate Specificity; Xenograft Model Antitumor Assays

2014