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.
CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme’s natural substrate, adenosine 5′-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.
Radical allylations represent effective routes to various alkenes, but to date they have relied chiefly on organostannane derivatives and still suffer from significant limitations with respect to the substitution pattern of the starting allylating agent. Indeed, while substituents at the β-position relative to the radical leaving group are well-tolerated, introduction of α-substituents induces a major complication due to the rapid and usually irreversible isomerization of the starting allylating agents. Although a number of research groups have made substantial efforts to develop heavy-metal-free radical allylations, methods compatible with α-substitution of the allylating agent are still scarce. Furthermore, quite a few systems are limited by the relative inaccessibility of the substrates. This Account summarizes our sustained efforts regarding the development of allylic alcohols into "ideal" radical allylating agents and presents published as well as some unpublished results. The systems we have developed combine the use of readily available xanthates and allylic alcohol derivatives under metal-free conditions to furnish not only alkenes but also aldehydes and saturated and unsaturated ketones through the virtually unprecedented homolytic cleavage of the normally strong C-O or C-C bond. The former route hinges on first converting the allylic alcohol into a 2-fluoro-6-pyridoxy derivative by reacting the corresponding alcoholate with 2,6-difluoropyridine, while the latter relies on attaching a cumyl group to the carbon bearing the free allylic alcohol. Either substrate is then exposed to the action of a suitable xanthate in the presence of a stoichiometric amount of a peroxide, usually lauroyl peroxide (DLP) in refluxing ethyl acetate or di-tert-butyl peroxide (TBHP) in refluxing chlorobenzene for the more difficult cases. Even though C-O or C-C bond homolysis leads to a stabilized 2-fluoro-6-pyridinyloxyl radical or a cumyl radical, respectively, the β-scission in both cases is relatively slow and at the lower limit of useful elementary radical steps. The kinetic barrier of the fragmentation can nevertheless be overcome because of the long relative lifetime of radicals generated by the degenerate transfer of the xanthate group, and this is a key element for success. This novel technology offers numerous advantages. The starting activated allylic alcohol derivatives are readily accessible in two steps from aldehydes or ketones. They can also be obtained by base-induced opening of epoxides. Numerous functional groups are tolerated under the mild reaction conditions for the radical addition-elimination, as nicely illustrated by over 150 examples of radical allylations, not all of which can be included in the present Account. In addition, substitution at both the α- and β-positions of the allylating agent is possible, a rare feature in this area.
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