An AKR1C3-activated kinase inhibitor prodrug

Enzymatically activated prodrugs can enable context-specific target inhibition. AKR1C3 is an NADPH-dependent aldo-ketoreductase involved in androgen metabolism, prostaglandin synthesis, and cell proliferation that is overexpressed in tumors, making it an ideal candidate for tumor-specific prodrug activation. Reported prodrugs that exploit AKR1C3 catalytic activity release DNA-intercalating toxins or other non-selective poisons upon enzymatic activation. OBI-3424, a prodrug of a DNA alkylating agent, is a prominent example of this strategy. To extend this concept to selective enzymatic inhibitors, we have developed AKR1C3-activated prodrugs of OTS964, a CDK11 inhibitor. We have probed the activities of the compounds with biochemical and cellular assays, finding specific activation of the lead prodrug by AKR1C3. Upon enzymatic conversion, the compound recapitulates the cellular activity of the parent compound. These results demonstrate that the AKR1C3-activated prodrug strategy can be used to convert selective kinase inhibitors into context-dependent prodrugs. Extension of this approach may enable synthesis of prodrugs for targeted therapies that spare normal tissue, further improving their therapeutic windows.