2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors
Graphical abstract
Section snippets
Acknowledgments
This work was funded by Mars, Incorporated. We thank the IGBMC Structural genomics platform staff (in particular Pierre Poussin-Courmontagne and Dr. Alastair McEwen). Infrastructures used in this research were supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale, the Hôpital Universitaire de Strasbourg (H.U.S) and the Université de Strasbourg.
References and notes (15)
Br. J. Pharmacol.
(2009)- et al.
Circ. Res.
(2008)et al.Curr. Mol. Med.
(2008)et al.Front. Biosci. (Schol. Ed).
(2011)et al.Biochemistry
(2003)Expert Rev. Clin. Pharmacol.
(2010)et al.Wound Repair Regen.
(2003)et al.Immunology
(2003) - et al.
Biochemistry
(2010)et al.PLoS Negl. Trop. Dis.
(2012) - et al.
J. Am. Chem. Soc.
(1997) Acc. Chem. Res.
(2005)- et al.
J. Med. Chem.
(2011) - Van Zandt, M.; Golebiowski, A.; Ji, M. K.; Whitehouse, D.; Todd, R.; Beckett, P. WO 2011...
Cited by (25)
Arginase: An emerging and promising therapeutic target for cancer treatment
2022, Biomedicine and PharmacotherapyCitation Excerpt :ABH and BEC, another two well-known arginase inhibitors derived from the boronic acid, can bind to the active manganese site of arginase, leading to the competitive inhibition of arginase activity [150], exhibiting high affinities for arginase (Ki of 0.11 and 0.4–0.6 mM on rat ARG1, respectively) [151,152]. The binding networks of ABH and BEC differ between ARG1 and ARG2, especially ABH shows much lower selectivity for ARG1against ARG2 [153]. Unfortunately, these compounds exhibited low oral bioavailability (5%) with undetectable plasma levels, even intraperitoneal administration led to only 50% bioavailability in multi-dose experiments[154].
Boronic acid-based arginase inhibitors in cancer immunotherapy
2020, Bioorganic and Medicinal ChemistryCitation Excerpt :Both compounds inhibited human ARG-1/2 in the range of 251 to 1000 nM.65 Apart from the mentioned inhibitors, there are many compounds with other substituents in the side chain, but their activities were lower.64–72 The first series of compounds with rigid conformation as the third-generation was compounds designed and synthesized by Mars, Inc./IPD Inc.
Insights on the participation of Glu256 and Asp204 in the oligomeric structure and cooperative effects of human arginase type I
2020, Journal of Structural BiologyCitation Excerpt :In higher animals, and especially in human, arginase exists in two isoenzymatic forms, which differ in their cellular distribution and physiological function (Yu et al., 2003). Between the two isoenzymes there is a 55% identity at amino acid sequence level, and all residues that have been defined as critical or essential for the binding of substrate and the activator metal, as well as for the catalysis itself (Golebiowski et al., 2013; Perozich et al., 1997) are conserved. Both isoenzymes, and especially arginase type I, have been associated with pathological alterations as hyperammonemia and growth retardation, in addition to other complications.
Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158
2020, Journal of Structural Biology: XCitation Excerpt :In addition, the boronic acid functionality of ABH may display cross-reactivity towards other proteins, causing potential toxicity (Ivanenkov and Chufarova, 2014). Recently, efforts aiming at the improvement of ABH for cancer immunotherapy have resulted in the development of the Arginase-1 inhibitor CB-1158 (INCB001158) by Calithera Biosciences, Inc. (South San Francisco, CA) (Steggerda et al., 2017; Golebiowski et al., 2013; Van Zandt et al., 2013; Golebiowski et al., 2013). CB-1158 is an orally bioavailable inhibitor, which reportedly inhibits human Arginase-1 in a biochemical assay with a half-maximal inhibitory concentration (IC50) of 86 nM (Steggerda et al., 2017).
Rational design of novel irreversible inhibitors for human arginase
2018, Bioorganic and Medicinal ChemistryCitation Excerpt :The inhibitors bind to the active site of arginase, and react with a Mn+2 bound hydroxide ion to give a tetrahedral boronate species. These boronic acid inhibitors often have high toxicity, and relatively poor pharmacokinetic profiles, selectivities and bioavailabilities.16,17 Thus, their potential applications as chemotherapeutic reagents are limited.