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tamoxifen (tamoxifen, Douglas)

✓ Approved

Douglas Pharmaceuticals Limited · ESR1 · Small Molecule

What is tamoxifen?

tamoxifen is a small molecule developed by Douglas Pharmaceuticals Limited. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand Namestamoxifen, Douglas
CompanyDouglas Pharmaceuticals Limited
Drug ClassSmall Molecule
Molecular TargetESR1
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, Douglas Pharmaceuticals Limited

Mechanism of Action

Molecular Targets

tamoxifen acts on 1 molecular target:

ESR1estrogen receptor 1 (ER, ESR)
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Therapeutic Indications

tamoxifen is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Neoplasms benign, malignant and unspecified (incl cysts and polyps)Breast cancer✓ Approved

Related Research Articles

PubMedMethodsX2026-05-25

Technical implementation for african pharmacogenetic studies on CYP2D6 from archived breast cancer formalin fixed paraffin-embedded (FFPE) tissues.

Nthontho Keneuoe Cecilia KC, Tawe Leabaneng L, Mugo Nduta N, Mabaka Rorisang R et al.

Breast cancer remains the most common cancer affecting women globally, with a disproportionate impact on low- and middle-income countries (LMICs), where survival is poor despite lower incidence. Conducting molecular studies in these settings is often hampered by limited resources and technical challenges, particularly when using traditional DNA sources. This is also true for pharmacogenetic studies among Africans. For this, we propose novel CYP2D6 PCR protocols optimized for formalin-fixed paraffin-embedded (FFPE) tissue blocks, a readily available and accessible resource in LMICs. Although formalin fixation can cause DNA fragmentation, FFPE tissues offer a valuable source for genetic studies.•We introduce four nested PCR-RFLP approaches targeting CYP2D6 variants for *2, *4, *17, *29 alleles (rs16947, rs3892097, rs28371706, rs59421388), which influence drug metabolism, in particular tamoxifen (breast cancer treatment)•Additionally, two amplification-refractory mutation system (ARMS) protocols are proposed to detect variants that determine CYP2D6*2 (rs5758550) and CYP2D6*29 (rs61736512) that lack suitable cleavage sites.This workflow aims to demonstrate the feasibility of pharmacogenetic studies in LMICs using FFPE samples, providing alternative techniques to traditional methods. Understanding CYP2D6 genetic variations is crucial in African populations, where tamoxifen metabolism impacts treatment efficacy. This research could improve personalized therapy and reduce mortality disparities in sub-Saharan Africa.

PMID 42181075
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PubMedbioRxiv : the preprint server for biology2026-05-25

Endocrine therapy-specific lineage and partial epithelial-mesenchymal reprogramming defines divergent resistant cell-states in ER+ breast cancer.

Sahoo Sarthak S, Khanna Sejal S, Senapati Swayamshree S, Kumar Hemant H et al.

Acquired resistance to endocrine therapy remains a primary obstacle in the clinical management of estrogen receptor-positive (ER+) breast cancer. While resistance is frequently accompanied by transcriptional rewiring and lineage plasticity, how specific pharmacological modalities dictate divergent resistance trajectories remains poorly understood. Here, we integrate multi-omic profiling, spanning bulk and single-cell transcriptome, chromatin architecture (Hi-C), and the cistrome, to systematically compare the mechanisms involved in adaptive resistance to selective estrogen receptor modulators (SERMs, e.g., tamoxifen) and degraders (SERDs, e.g., fulvestrant), and the mechanism driven by constitutive ESR1 mutation, to characterize how mode of ERα perturbation influences lineage identity and epithelial-mesenchymal state. We found that tamoxifen resistant (TamR) cells occupy a distinct transcriptional state characterized by coordinated luminal erosion, partial basal lineage activation, and stabilization of a partial epithelial-mesenchymal (pEMT) program. In contrast, fulvestrant resistant (FulR) cells primarily suppress ER signaling without extensive lineage reprogramming. Finally, ESR1 mutant cells recapitulate ligand-driven ER hyperactivation with limited engagement of mesenchymal and basal gene expression programs. Chromatin profiling further revealed that SERM resistance is accompanied by higher-order genome reorganization, including A-to-B compartment switching at luminal regulators such as GATA3 and ESR1, redistribution of ERα and FOXA1 binding, and consequent activation of a pEMT program. Furthermore, we show that SERM-induced reprogramming is accompanied by a distinct mode of immune evasion where the reprogrammed cells do not engage classical T-cell exhaustion programs but instead exhibit coordinated loss of major histocompatibility complex (MHC) class I antigen presentation and establishment of a pro-tumorigenic signaling that strongly predicts adverse survival outcomes in patient cohorts. Together, these findings indicate that endocrine resistance does not converge on a single molecular endpoint but instead reflects drug-specific adaptive states defined by ER signaling context, lineage identity, and chromatin architecture. Our study establishes the basal-pEMT axis as a coordinated, epigenetically encoded module of SERM-induced plasticity and reframes endocrine resistance as a multidimensional evolutionary process shaped by therapeutic mechanisms of action.

PMID 42182314
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PubMedbioRxiv : the preprint server for biology2026-05-25

TMEM119+ microglia MHC class I restricted antigen presentation impacts CD8 T cell memory, effector status, and blood-brain barrier disruption during neurotropic virus infection.

Seady Marina M, Maynes Mark A MA, Thelwell Javonte S JS, Jin Fang F et al.

The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection has been difficult to define. Using Theiler's murine encephalomyelitis virus (TMEV) infection of neurons as a model system, our laboratory has previously determined that H-2D b restricted, but not H-2K b restricted CD8 T cells are required for viral clearance, demonstrating the role of discrete MHC class I alleles. To determine the extent microglia antigen presentation impacts brain-infiltrating CD8 T cells, our laboratory generated novel single MHC class I conditional knockout mice in which H-2K b or H-2D b can be specifically deactivated in TMEM119+ microglia with tamoxifen administration. During TMEV infection, conditional knockout of H-2K b in microglia reduced antigen-specific CD8 T cell proliferation in the brain. Meanwhile, mice with deletion of D b in microglia had reduced levels of perforin in antigen-specific CD8 T cells. Furthermore, microglia specific deletion of H-2D b reduced CD8 T cell numbers in the brain and preserved blood-brain barrier (BBB) integrity. Microglial D b restricted antigen presentation was also essential for the reactivation of CD8 tissue resident memory (TRM) cells and BBB integrity during memory recall responses. These findings further our understanding of how brain infiltrating antiviral CD8 T cell responses are impacted by microglia, as well as define how this cellular interaction contributes to BBB disruption during neuroinflammation. These findings also have high significance to our understanding of how microglia impact CD8 TRM cell populations that reside in the brain long after virus infection is cleared.

PMID 42182166
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PubMedCancer letters2026-05-24

Tamoxifen enhances radiation efficacy by promoting M1 polarization of tumor associated macrophages via JNK/c-JUN pathway.

Ma Shuangshuang S, Chen Minxin M, Sun Xiaozheng X, Wei Baochao B et al.

Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tumor microenvironment (TME), however, remains a major obstacle to the efficacy of radiotherapy. Whether high-dose tamoxifen can reprogram TME to synergistically enhance radiation efficacy is still ambiguous. Here, we have found high-dose tamoxifen could dramatically enhance radiation-induced antitumor effects without significant side effects in immunocompetent mice. Flow cytometry and multiplex immunofluorescence experiments revealed that radiation combined with tamoxifen resulted in significant enrichment of effector CD8+ T cells and M1 tumor associated macrophages (TAMs). While depletion of TAMs and CD8+ T cells impaired the synergistic antitumor effects mediated by combination treatment of radiation and tamoxifen. Furthermore, spatial proximity analysis demonstrated a dramatically reduced nearest-neighbor distance between CD8+ T cells and M1-like TAMs in the combination group, indicating enhanced cellular interaction within the TME. In vitro experiments demonstrated that tamoxifen directly acted on TAMs, rather than CD8+ T cells, to promote M1 polarization and subsequently enhanced the activation and effector function of CD8+ T cells, regardless of ER expression in tumor cells and macrophages. Mechanistically, RNA-sequencing and experimental validation uncovered that tamoxifen and tumor cell-derived TNF-α and IL-1β after irradiation synergistically activated the JNK/c-JUN pathway and promoted M1 polarization of TAMs. In conclusion, our study revealed the immunomodulatory effects of high-dose tamoxifen in the context of radiation and provided preclinical evidence for combination therapy of high-dose tamoxifen and radiotherapy in both ER-positive and ER-negative cancers.

PMID 42176795
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PubMedCancer treatment and research communications2026-05-24

The rise of selective estrogen receptor modulators (SERMs) in breast cancer therapy: a promising horizon.

Al-Zoubi Raed M RM, Garada Khalil K, Zarour Ayman A AA, Elaarag Mai M et al.

Despite advancements in breast cancer treatment, breast cancer is still among the major causes of cancer-related deaths worldwide, with most breast cancers being estrogen receptor positive (ER+). Selective estrogen receptor modulators (SERMs) have been the core drug class used in endocrine therapy for ER+ breast cancer through tissue-specific conformational changes to the estrogen receptor. The present study critically evaluates the pharmacologic development, thermodynamics, and clinical effectiveness of SERMs. We systematically analyze approved agents (e.g., tamoxifen, raloxifene, bazedoxifene), investigational drugs (e.g., endoxifen, lasofoxifene), and historically discontinued compounds to understand the structural basis of their clinical successes and failures. Furthermore, we explore the molecular drivers of SERM resistance, including ESR1 mutations, epigenetic reprogramming, and growth factor cross-talk. By highlighting the limitations of early-generation SERMs, such as paradoxical partial agonism, thromboembolic risks, and acquired resistance, we provide a rationale for the current paradigm shift toward Complete Estrogen Receptor Antagonists (CERANs) and oral Selective Estrogen Receptor Degraders (SERDs), offering critical insights into the future of precision endocrine oncology.

PMID 42176550
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PubMedEuropean journal of medicinal chemistry2026-05-23

Developing orally active estrogen receptor degraders by conjugation of boronic tamoxifen and cereblon ligands.

Peng Xianyou X, Hossain Ahamed A, Ma Peng P, Guo Shanchun S et al.

Degradation of estrogen receptor has been clinically proven effective in treating ER+ breast cancer. Proteolysis-Targeting Chimeras (PROTACs) can degrade a target protein by engaging both the target protein and the E3 ligase, bringing them into close physical proximity to effect ubiquitination and proteasomal degradation. We report the design and construction of ER PROTACs that link tamoxifen derivatives to a CRBN E3 ligand to achieve ER protein degradation. The ER degrading efficacy of the synthesized PROTACs was found to depend on the ER binding affinity, the linker structure, and the E3 ligand. Tamoxifen-4-boronic acid conjugated to lenalidomide through a rigid piperidine-methylene-piperazine linker was found to yield degraders that show nanomolar antiestrogenic potency and excellent oral bioavailability. The most active ER degrader with good pharmacokinetic profile, 4r, showed remarkable in vivo efficacy in blocking ER+ (both non-mutant and Y537S mutant) breast tumor growth as a monotherapy or in combination with CDK4/6 inhibitors.

PMID 42172929
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