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Two-drug trick to target the brain blocks toxicity in the body

When combined, two drugs alter the activity of a protein complex called target of rapamycin complex 1 such that it is inhibited in the brain but not the body, enabling the treatment of brain tumours in mice without systemic toxicity.
  1. Matthias P. Wymann

    1. Matthias P. Wymann is in the Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland.

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  2. Chiara Borsari

    1. Chiara Borsari is in the Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland.

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Medicinal chemists and pharmacologists dream about how drugs might be directed specifically to selected organs. A particularly challenging target is the brain: many drugs do not pass easily through the blood–brain barrier (BBB), or are actively pumped out of the brain. The situation is complicated further when a drug to be delivered also shows body-wide (systemic) adverse effects. One such drug is rapamycin, which blocks tumour growth, but is also used as an immunosuppressant during organ transplantation1. Rapamycin and its semi-synthetic derivatives, dubbed rapalogs, inhibit a protein complex called target of rapamycin complex 1 (TORC 1). Writing in Nature, Zhang et al.2 present an innovative chemical approach to confine the action of rapalogs to the brain, and thereby eliminate undesirable systemic effects such as immunosuppression. They combine a high-affinity rapalog (RapaLink-1) with a newly developed molecule (RapaBlock) that prevents TORC1 inhibition systemically, but cannot enter the brain.

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Nature 609, 681-683 (2022)

doi: https://doi.org/10.1038/d41586-022-02892-5

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Competing Interests

The authors declare no competing interests.

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