Construction of Hybrid Inhibitors for Metalloproteinase Targeting.
Quinto, Laura B.
- Although cancer-promoting activities of extracellular proteases and peptidases in the tumor microenvironment are well known, the disruption of individual enzymes in this environment remains a fundamental challenge. To better understand the roles of these enzymes in cancer progression, and to potentially begin to target them in vivo, selective inhibitors of these enzymes are needed. Small molecules... read more, which have proven potent inhibitors of these enzymes, are rarely selective enough to target an individual enzyme. Antibodies can exhibit exemplary selectivity of binding, but inhibitory clones are difficult to isolate. This work explores a novel strategy for selective, effective inhibition of such enzymes, in which a specific protein binder is conjugated to an inhibitory small molecule. To this end, antibodies against a model antigen, matrix metalloproteinase-9 (MMP-9) were identified and site-specifically modified for conjugation to an inhibitory small molecule. Candidate small molecules were also identified and evaluated for inhibitory efficacy. Then, conditions to efficiently conjugate the two moieties were explored and leveraged to produce candidate hybrid inhibitors. We anticipate that this strategy will provide a robust method of producing selective inhibitors for broad classes of enzymes active in the tumor microenvironment and in other complex diseases.read less