title: Identification of potent and selective MTH1 inhibitors.
abstract: Structure based design of a novel class of aminopyrimidine MTH1 (MutT homolog 1) inhibitors is described. Optimization led to identification of IACS-4759 (compound 5), a sub-nanomolar inhibitor of MTH1 with excellent cell permeability and good metabolic stability in microsomes. This compound robustly inhibited MTH1 activity in cells and proved to be an excellent tool for interrogation of the utility of MTH1 inhibition in the context of oncology.
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA. Electronic address: apetrocchi@mdanderson.org.
authors.forename: Alessia
authors.initials: A
authors.lastname: Petrocchi
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Leo
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Naphtali J
authors.initials: NJ
authors.lastname: Reyna
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hamilton
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Shi
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Connor A
authors.initials: CA
authors.lastname: Parker
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Faika
authors.initials: F
authors.lastname: Mseeh
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Bardenhagen
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Leonard
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Cross
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Yongying
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Draetta
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Marszalek
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Jones
authors.affiliation: Institute for Applied Cancer Science, MD Anderson Cancer Center, 1901 East Road, Houston (TX) 77054, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
mesh_terms: D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes
keywords: 2-Aminopyrimidine; Antitumor; IACS-4759; MTH1 inhibitors