Searching for an ideal SERM: Mining tamoxifen structure-activity relationships

Sky Price; Sophie G Bender; Rachel Yahn; Nicholas A Till; Sophia Varady; Rebecca Lyn LaLonde

doi:10.1016/j.bmcl.2021.128383

Searching for an ideal SERM: Mining tamoxifen structure-activity relationships

Bioorg Med Chem Lett. 2021 Nov 15:52:128383. doi: 10.1016/j.bmcl.2021.128383. Epub 2021 Sep 27.

Authors

Sky Price¹, Sophie G Bender², Rachel Yahn³, Nicholas A Till³, Sophia Varady³, Rebecca Lyn LaLonde⁴

Affiliations

¹ Chemistry Department, Reed College, 3203 SE Woodstock Blvd, Portland, OR, USA; Department of Chemistry, University of Texas at Austin, 2506 Speedway, Austin, TX USA.
² Chemistry Department, Reed College, 3203 SE Woodstock Blvd, Portland, OR, USA; Department of Chemistry and Chemical Biology, Cornell University, 122 Baker Laboratory, Ithaca, NY, USA.
³ Chemistry Department, Reed College, 3203 SE Woodstock Blvd, Portland, OR, USA.
⁴ Chemistry Department, Reed College, 3203 SE Woodstock Blvd, Portland, OR, USA. Electronic address: rlalonde@reed.edu.

PMID: 34592434
DOI: 10.1016/j.bmcl.2021.128383

Abstract

The repurposing of old drugs for new treatments has recently garnered increased attention in the face of new diseases and declining productivity of the pharmaceutial industry. This report draws attention to potential opportunities hiding in plain sight within the SAR of off-patent drugs. Herein we explore the untapped potential of Selective Estrogen Receptor Modulators (SERMs). SERMs are a class of molecules that have been highly influential in the treatment of estrogen receptor-positive breast cancers. However, the most commonly prescribed SERM, tamoxifen, has been found to increase the risk of endometrial cancer. Another SERM, raloxifene, does not increase incidence of endometrial cancer, but has been abandoned as a breast cancer treatment. We report the design, synthesis, and evaluation of an unexplored tamoxifen substitution pattern which mimics the geometry of raloxifene to confer its favorable pharmacodynamics. This substitution pattern was found to maintain excellent binding affinity to estrogen receptor-α.

Keywords: Breast cancer; Estrogen receptor alpha; Raloxifene; Selective estrogen receptor modulators; Tamoxifen.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Hormonal / chemistry
Antineoplastic Agents, Hormonal / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Dose-Response Relationship, Drug
Estrogen Receptor alpha / antagonists & inhibitors*
Estrogen Receptor alpha / metabolism
Female
Humans
Molecular Structure
Raloxifene Hydrochloride / chemistry
Raloxifene Hydrochloride / pharmacology*
Selective Estrogen Receptor Modulators / chemistry
Selective Estrogen Receptor Modulators / pharmacology*
Structure-Activity Relationship
Tamoxifen / chemistry
Tamoxifen / pharmacology*

Substances

Antineoplastic Agents, Hormonal
ESR1 protein, human
Estrogen Receptor alpha
Selective Estrogen Receptor Modulators
Tamoxifen
Raloxifene Hydrochloride