4HXX

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1

Summary for 4HXX

• Entry DOI: 10.2210/pdb4hxx/pdb
• Descriptor: Methionine aminopeptidase 1, COBALT (II) ION, POTASSIUM ION, ... (6 entities in total)
• Functional Keywords: aminopeptidases, pyrimidines, pyrimidyl group, pyridinylpyrimidine, cell cycle, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35093.40

Authors

Gabelli, S.B.,Zhang, F.,Liu, J.,Amzel, L.M. (deposition date: 2012-11-12, release date: 2013-04-03, Last modification date: 2024-02-28)

Primary citation

Zhang, P.,Yang, X.,Zhang, F.,Gabelli, S.B.,Wang, R.,Zhang, Y.,Bhat, S.,Chen, X.,Furlani, M.,Amzel, L.M.,Liu, J.O.,Ma, D.
Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.
Bioorg.Med.Chem., 21:2600-2617, 2013

PubMed 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.

PubMed: 23507151
DOI: 10.1016/j.bmc.2013.02.023

Experimental method

X-RAY DIFFRACTION (2.09 Å)