Rapamycin

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Rapamycin can be used as a targeted anti-cancer drug and works as a non-competitive enzyme inhibitor[1].

Rapamycin binds to the FKBP12 protein at an allosteric site. The FKBP is bound to an mTOR enzyme near the C terminus, and the binding of rapamycin to FKBP changes the shape of the ATP binding site of the mTOR. Therefore, phosphorylation of the target proteins, s6k and 4EBP1, cannot occur, because phosphate cannot be produced from ATP - the kinase has been inhibited[2]

Rapamycin, although very efficient and powerful at targetting cancer, is not used too often due to the cost. One 30 ml tube of the ointment containing only one rapamycin tablet can cost up to $3000[3].

Rapamycin only inhibits mTORC1 and not mTORC2, and mTORC2 also controls pathways that regulate cell growth and proliferation, so it does not provide complete inhibition of the mTOR complex. Furthermore, some studies suggest that inhibition of mTORC1 and not mTORC2 could actually upregulate the Akt pathway (which is dysregulated in many cancerous cells) through a negative feedback loop[4].

Rapamycin is also insoluble and difficult to source, but synthetic analogues of Rapamycin (known as Rapalogues) that are more soluble have been created to have better pharmalogical properties[5]

References

  1. Gajanan V. Sherbet. Molecular Approach to Cancer Management. 1st Edition. Published 2017.
  2. 8. Tao Z, Barker J, Shi SD, Gehring M, Sun S. Steady-state kinetic and inhibition studies of the mammalian target of rapamycin (mTOR) kinase domain and mTOR complexes. Biochemistry. Published 2010. Volume 49, Issue 39, Pages 8488-98.
  3. Bhushan Madke. Topical rapamycin (sirolimus) for facial angiofibromas. Indian Dermatol Online J. Published 2013. Volume 4, Issue 1, Pages 54-57. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573457/
  4. Hayman, TJ; Kramp, T; Kahn, J; Jamal, M; Camphausen, K; Tofilon, DJ. Translation Oncology, 2013
  5. Garcia-Echeverria, C. Allosteric and ATP Competitive inhibitors of mTOR for cancer treatment. Bioorganic and medicinal chemistry letters, 2010.

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