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PIPELINE > TRIAL OVERVIEW

Molecule Overview
Next-Generation PI3Kα Inhibitor
LY4045004
Next-Generation PI3Kα Inhibitor

Vasan N, et al1; Engelman JA, et al2; Dirican E, et al3

Target

Phosphoinositide 3-kinase alpha (PI3Kα) molecules harboring activating mutations are oncogenic drivers found in approximately 40% of hormone-receptor-positive (HR+) breast cancers and less commonly in other cancers.3,4  The most common mutations include H1047R in the kinase domain, and E545K and E542K in the helical domain.4,5 Alterations in the PI3K signaling pathway have been associated with endocrine therapy resistance in HR+ breast cancer.6

Molecule

LY4045004 is an allosteric, mutant-selective inhibitor of PI3Kα with H1047R or helical PI3Kα mutations. It has shown preclinical activity in PI3Kα H1047R, E545K, and E542K-driven breast cancer models. Due to its mutant to wildtype ratio of PI3Kα selectivity at efficacious dose levels, LY4045004 is expected to be well tolerated and show a high safety margin.7

Clinical Development

LY4045004 preclinical data support further evaluation in clinical trials.7

References

  1. Vasan N, et al. Ann Oncol. 2019;30(Suppl_10):x3-x11.
  2. Engelman JA, et al. Nat Rev Genet. 2006;7(8):606-619.
  3. Dirican E, et al. Tumour Biol. 2016;37(6):7033-7045.
  4. Martinez-Saez O, et al. Breast Cancer Res. 2020;22(1):45.
  5. Zhao L, Vogt PK. Proc Natl Acad Sci U S A. 2008;105(7):2652-2657.
  6. Tokunaga E, et al. Breast Cancer. 2006;13(2):137-144.
  7. Gilmour R, et al. Abstract presented at: San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract P4-12-24.
For information on trial enrollment, locations, and more, call 1-800-545-5979.
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