5′- <i>S</i> -(3-Aminophenyl)-5′-thioadenosine, a Novel Chemoprotective Agent for Reducing Toxic Side Effects of Fluorouracil in Treatment of MTAP-Deficient Cancers

Nucleobase analogue (NBA) drugs, such as 5-fluorouracil (5-FU), are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests that the use of S-methyl-5'-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We hypothesized that an MTA analogue can retain the protective function of MTA without undesired side effects. We screened a library of MTA analogues and identified 5'-S-(3-aminophenyl)-5'-thioadenosine (m-APTA) as a substrate of MTAP that could be converted to adenine, a necessary step for protection of normal cells from NBA toxicity. It selectively protected MTAP-expressing cells from 5-FU toxicity while it did not interfere with the cytotoxicity of 5-FU on isogenic MTAP-deficient cell lines. At effective dose, m-APTA protected the mouse hosts from 5-FU-induced toxicity (i.e., anemia) without the induction of hypothermia. Importantly, m-APTA provided host protection without compromising the efficacy of 5-FU on MTAP-deficient bladder cancer xenografts. In silico docking studies revealed that, unlike MTA, m-APTA interacts inefficiently with adenosine A1 receptor, providing a plausible explanation of the superior safety profile of m-APTA. Therefore, m-APTA can significantly improve the translational potential of the combination treatment strategy that selectively reduces NBA toxicity in normal cells while targeting MTAP-deficient cancers.