Small Molecule Inhibitors 51 Rationale

Small molecule telomerase inhibitors are an attractive approach because it should be possible to intervene at multiple levels within the pathways that activate telomerase. Both known and unknown signaling pathways converging on either promoter are candidates for inhibition, and selective active site inhibitors also have considerable potential. Additionally, the telomere itself and various other targets that we discuss later in the chapter should be amenable to drugging. Small molecules are likely to demonstrate favorable bioavailability and frequently have the manufacturing advantages of cost-efficient, reproducible, and scalable synthesis. Importantly, they are also easily amenable to classic medicinal chemistry for lead optimization, and small molecule pharmacokinetics can easily be established in early trials. However, direct inhibitors of telomerase activity are likely to be subject to the phenotypic lag, which must be taken into account when planning preclinical models or trial endpoints. Additionally, signal transduction inhibitors may not exhibit their primary anti-neoplastic effects via telomerase, but rather through other targets modulated by the pathway that is inhibited. Therefore, it is important to consider the most relevant molecular markers of activity.

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