D-15414 Explained

D-15414 is a nonsteroidal weak estrogen of the 2-phenylindole group which was never marketed.^[1] It is the major metabolite of the selective estrogen receptor modulator (SERM) zindoxifene (D-16726).^[2] D-15414 has high affinity for the estrogen receptor (ER) and inhibits the growth of ER-positive MCF-7 breast cancer cells in vitro. However, contradictorily, subsequent research found that the drug produced fully estrogenic effects in vitro similarly to but less actively than estradiol, with no antiestrogenic activity observed.^[3] The reason for the discrepancy between the findings is unclear, though may be due to methodology. The unexpected estrogenic activity of D-15414 may be responsible for the failure of zindoxifene in clinical trials as a treatment for breast cancer.^[4]

Notes and References

1. Book: Jordan VC, Tormey DC . Antiestrogen Therapy for Breast Cancer . Cancer Treatment and Research . Endocrine Therapies in Breast and Prostate Cancer . 39 . 97–110 . 1988 . 2908611 . 10.1007/978-1-4613-1731-9_7 . 978-1-4612-8974-6.
2. von Angerer E, Prekajac J, Berger M . The inhibitory effect of 5-acetoxy-2-(4-acetoxyphenyl)-1-ethyl-3-methylindole (D 16726) on estrogen-dependent mammary tumors . European Journal of Cancer & Clinical Oncology . 21 . 4 . 531–537 . April 1985 . 3924626 . 10.1016/0277-5379(85)90048-3 .
3. Robinson SP, Koch R, Jordan VC . In vitro estrogenic actions in rat and human cells of hydroxylated derivatives of D16726 (zindoxifene), an agent with known antimammary cancer activity in vivo . Cancer Research . 48 . 4 . 784–787 . February 1988 . 3338076 .
4. Book: Maximov PY, McDaniel RE, Jordan VC . Tamoxifen: Pioneering Medicine in Breast Cancer. 23 July 2013. Springer Science & Business Media. 978-3-0348-0664-0. 170–.