No abstract

Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure−activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (K i = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.

No abstract

Sixteen compounds of the general structure {HON: CH.C5H4N+ CCHf1].R+}2Br-have been synthesized in which the position of the oxime group in the pyridine ring, the second charged group R+ and the number of methylene groups between the charged atoms have been varied.The rate at which these compounds reactivate cholinesterase inhibited by ethyl pyrophosphate has been studied and a number have been found which are more active than 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate. Since considerable variation in structure was found among those compounds which are better reactivators than the latter, the concept that 2-hydroxyiminomethyl-N-methylpyridinium salts are unique in their ability to fit the surface of the inhibited enzyme is no longer tenable. The reactivating power of these oximes correlated well with their ability, when given in conjunction with atropine, to save the lives of mice poisoned by ethyl pyrophosphate. The most effective compounds, NN'-trimethylenebis-(4-hydroxyiminomethylpyridinium bromide) and NN'-hexamethylenebis(2-hydroxyiminomethylpyridinium bromide), contained a further oxime group in R+, but the second oxime group was not essential for high activity. These new oximes were also superior in saving the lives of mice poisoned with sarin (isopropyl methylphosphonofluoridate), but the improvement was not as dramatic as when the mice were poisoned with ethyl pyrophosphate. The toxicity of the compounds varied with both n and R+ and was unrelated to the therapeutic potency.

This work was carried out in 1948-9 and formed the subject of confidential reports to the Ministry of Supply. It was part of a search for simple compounds which would protect cholinesterases against inhibition by such compounds as Tabun (ethyl NN-dimethylphosphoramidocyanidate), Sarin (isopropyl P-methylphosphonofluoridate) and ethyl-Sarin (iopropyl P-ethylphosphonofluoridate). As with DFP (dii8opropyl phosphorofluoridate: Mackworth & Webb, 1948) inhibition by Tabun (Augustinsson, 1951, 1953) and Sarin (unpublished work of A. Todrick & L. T. D. Williams) is irreversible, and it is reasonable to suppose that inhibition by ethyl-Sarin is also irreversible. The starting point of our experiments was the supposition that since nothing definite was known about the active centre of cholinesterases, the catalytic activity was probably associated with the amino acid side chains. A number of amino acids were examined for their ability to protect cholinesterase in vitro; only dopa (3:4-dihydroxyphenylalanine) was effective, but in high concentration, and it was found that protective ability was a property of catechol derivatives. It appears that Augustinsson (1952), independently and about the same time, discovered the reaction of catechols with Tabun, and published his results almost simultaneously with those of Jandorf, Wagner-Jauregg, O'Neill & Stolberg (1952) on the reaction of phenols with DFP. The present paper deals mainly with the properties of Sarin, but sufficient data are also given to make it clear that the three groups of workers have studied different facets of the same phenomenon. A brief account of this work has been published (Berry, 1953). THEORETICAL One of us (A.T.) in earlier unpublished work on Sarin in collaboration with L. T. D. Williams considered the case of irreversible inhibition by a labile inhibitor. The gist of their treatment is as follows: