Identification of potent and selective MTH1 inhibitors
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Acknowledgments
We thank Barbara Czako, Maria Emilia Di Francesco, Michael Soth and Wylie Palmer for helpful discussion.
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2020, Acta Pharmaceutica Sinica BCitation Excerpt :In addition, it was demonstrated to be effective in both the in vitro studies and in vivo models including human colon cancer and chemotherapy-resistant patient-derived malignant melanoma mouse xenograft models, validating TH1579 as a promising inhibitor for cancer treatment26. On the basis of the structures of TH287 and TH588, Petrocchi et al.27 first designed an aminopyrimidine (AP) analogue, AP-1, as an inhibitor for MTH1 (IC50 = 4 μmol/L) with the aid of molecular modeling using Schrödinger GLIDE XP docking (Fig. 5). To alleviate desolvation penalty of the ligand and engage with the lipophilic cavity, a dimethyl group was added in the middle of the chain in AP-1 to provide the compound AP-2 having 26-fold improved inhibitory potency against MTH1 (IC50 = 0.14 μmol/L).
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Present address: Cancer Research Technology-Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
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