Overview of the Development of Glutaminase Inhibitors: Achievements and Future Directions

Abstract

It has been demonstrated that glutamine metabolism has become the main energy and building blocks supply for the growth and viability of a potentially large subset of malignant tumors. The glutamine metabolism often depends upon mitochondrial glutaminase (GLS) activity, which converts glutamine to glutamate and serves as a significant role for bioenergetic processes. Thus, recently, the GLS has become a key target for small molecule therapeutic intervention. Numerous medicinal chemistry studies are currently aimed at the design of novel and potent inhibitors for GLS, however, to date, only one compound (named CB-839) have entered clinical trials for the treatment of advanced solid tumors and hematological malignancies. The perspective summarizes the progress in the discovery and development of GLS inhibitors, including the potential binding site, biochemical techniques for inhibitor identification, and approaches for identifying small-molecule inhibitors, as well as future therapeutic perspectives in glutamine metabolism are also put forward in order to provide reference and rational for the drug discovery of novel and potent glutamine metabolism modulators.

The Warburg Effect 97 Years after Its Discovery

“…GLS inhibition has been also found to be efficient in combination therapy. The inhibition of the anti-apoptotic protein BCL-2 integrates glutaminase inhibition [ 222 ]. Furthermore, it has been shown that highly invasive ovarian cancer cells have increased glutamine dependence compared to less invasive cells [ 223 ], and metastatic prostate tumors show increased dependence on glutamine uptake [ 223 ].…”

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…JHU-083 is a newly synthesized prodrug of DON, which can be administered in an inert state and then be activated preferentially in the tumor microenvironment through enzymatic cleavage, thus alleviating the previously reported toxicity of DON (106,121). Other DON prodrugs such as Rais-5C and Nedelcovych-13d have also been reported (122)(123)(124). Unlike the glutamine mimetics, the allosteric inhibitors such as BPTES and CB-839, are selectively targeting glutaminase without disturbing other aspects of glutamine metabolism (25,124).…”

“…Other DON prodrugs such as Rais-5C and Nedelcovych-13d have also been reported (122)(123)(124). Unlike the glutamine mimetics, the allosteric inhibitors such as BPTES and CB-839, are selectively targeting glutaminase without disturbing other aspects of glutamine metabolism (25,124). BPTES is now the most frequently used allosteric glutaminase inhibitor, which specifically inhibits kidney type glutaminase activity through the formation of an inactive complex (125).…”

“…BPTES is now the most frequently used allosteric glutaminase inhibitor, which specifically inhibits kidney type glutaminase activity through the formation of an inactive complex (125). Though BPTES shows high specificity and efficiency in inhibiting cancer cell proliferation in vitro, the drawbacks of poor aqueous solubility and low bioavailability in vivo restrict its further applications in clinical trials (124). In order to improve drug solubility, several derivatives of BPTES were synthesized through structural modifications (119,(126)(127)(128).…”

Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

“…In addition to inhibiting glutamine uptake, in the past decade, research has focused on the antitumor effects of inhibition of glutaminase (GLS), the enzyme responsible for hydrolytic deamidation of glutamine to glutamate in the first enzymatic reaction of glutaminolysis. There are many small molecules that in recent years have proven to be capable of inhibiting GLS [ 107 , 108 ], such as the naturally occurring molecules 6-diazo-5-oxy-L-norleucine, azaserine, and acivicin, and the synthetic compounds BPTES, 968 and CB-839 [ 109 ] ( Figure 4 ). Among these, the compound CB-839 is a noncompetitive GLS inhibitor able to inhibit the entry of substrates into the TCA cycle, thus reducing cell viability and cancer stemness, increasing chemosensitivity, and inducing apoptotic cell death in several cancer types [ 110 , 111 , 112 , 113 , 114 ].…”