title: Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.
abstract: Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China.
authors.forename: Pengtao
authors.initials: P
authors.lastname: Zhang
authors.forename: Xinye
authors.initials: X
authors.lastname: Yang
authors.forename: Feiran
authors.initials: F
authors.lastname: Zhang
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Gabelli
authors.forename: Renxiao
authors.initials: R
authors.lastname: Wang
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bhat
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Chen
authors.forename: Manuel
authors.initials: M
authors.lastname: Furlani
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Dawei
authors.initials: D
authors.lastname: Ma
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D011743:Pyrimidines; D000626:Aminopeptidases; C506619:METAP1 protein, human