RET Inhibitor

Selpercatinib

RET_Inhibitor

Mulligan LM1

Target
Rearranged during transfection (RET) fusions have been identified in approximately 2% of non-small cell lung cancer,2,3 approximately 10% of papillary thyroid cancer,4,5 and less than 1% in other solid tumors including pancreatic and colorectal cancer.6-8  RET point mutations account for approximately 60% of medullary thyroid cancer.9-11 Cancers that harbor activating RET fusions or RET mutations depend primarily on this single constitutively activated kinase for their proliferation and survival. This dependency renders such tumors highly susceptible to small-molecule inhibitors targeting RET.
Molecule
Selpercatinib is a selective, potent, CNS-active small-molecule inhibitor of RET. Selpercatinib possesses nanomolar potency against diverse RET alterations, including RET fusions, activating RET point mutations, and acquired resistance mutations. Selpercatinib has been shown in vitro and in vivo to exhibit specificity for RET, with limited activity against other tyrosine kinases.12,13
Clinical Development
Selpercatinib is being investigated in clinical trials in patients with RET-associated medullary thyroid cancer, non-small cell lung cancer, papillary thyroid carcinoma, pediatric cancers, and other advanced solid tumors.

References

  1. Mulligan LM. Nat Rev Cancer. 2014;14:173-186.
  2. Lipson D, et al. Nat Med. 2012;18(3):382-384.
  3. Takeuchi K, et al. Nat Med. 2012;18(3):378-381.
  4. Drilon A, et al. Nat Rev Clin Oncol. 2018;15(3):151-167.
  5. Parimi V, et al. NPJ Precis Oncol. 2023;7(1):10.
  6. Yang SR, et al. Clin Cancer Res. 2021;27(5):1316-1328.
  7. Kohno T, et al. Carcinogenesis. 2020;41(2):123-129.
  8. Li AY, et al. Cancer Treat Rev. 2019;81:101911.
  9. Hofstra RM, et al. Nature. 1994;367(6461):375-376.
  10. Agrawal N, et al. Clin Endocrinol Metab. 2013;98(2):E364-E369.
  11. Taccaliti A, et al. Curr Genomics. 2011;12(8):618-625.
  12. Subbiah V, et al. Ann Oncol. 2018;29:1869-1876.
  13. Drilon A, et al. LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.
Clinical Development
Selpercatinib is being investigated in clinical trials in patients with RET-associated medullary thyroid cancer, non-small cell lung cancer, papillary thyroid carcinoma, pediatric cancers, and other advanced solid tumors.

References

  1. Mulligan LM. Nat Rev Cancer. 2014;14:173-186.
  2. Lipson D, et al. Nat Med. 2012;18(3):382-384.
  3. Takeuchi K, et al. Nat Med. 2012;18(3):378-381.
  4. Drilon A, et al. Nat Rev Clin Oncol. 2018;15(3):151-167.
  5. Parimi V, et al. NPJ Precis Oncol. 2023;7(1):10.
  6. Yang SR, et al. Clin Cancer Res. 2021;27(5):1316-1328.
  7. Kohno T, et al. Carcinogenesis. 2020;41(2):123-129.
  8. Li AY, et al. Cancer Treat Rev. 2019;81:101911.
  9. Hofstra RM, et al. Nature. 1994;367(6461):375-376.
  10. Agrawal N, et al. Clin Endocrinol Metab. 2013;98(2):E364-E369.
  11. Taccaliti A, et al. Curr Genomics. 2011;12(8):618-625.
  12. Subbiah V, et al. Ann Oncol. 2018;29:1869-1876.
  13. Drilon A, et al. LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.

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The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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