An open label phase 1/2A study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer.

Rathkopf, Dana E.; Saleh, Mansoor N.; Tsai, Frank; Bilen, Mehmet Asım; Rosen, Lee S.; Gottardis, Marco M.; Infante, Jeffrey R.; Adams, Bonne J.; Liu, Lilian; Theuer, Charles P.; Freddo, James L.; Agarwal, Neeraj

doi:10.1200/jco.2019.37.15_suppl.e16542

Cited by 3 publications

(5 citation statements)

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“…Enzalutamide, Apalutamide (A587V, F876L, F877L, G684A, K631T, L595M, Q920R, R630Q, T576A, T878A) [46,47] Darolutamide (A587V) [48] Darolutamide (F876L, F877L, W742L, T787A, W741L, T878A, L702H, H875Y) [48] Galaterone (F877L, T878A) [49] TRC253 (F877L) [50,51]. ARV-110 [52,53] ARCC-4 [54] * Clinical benefit/resistance proven in clinical trials.…”

Section: Acquired Castration Resistancementioning

confidence: 99%

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Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Jacob

Raj

Allison

et al. 2021

Cancers

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Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

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Section: Acquired Castration Resistancementioning

confidence: 99%

“…TRC253 is a high-affinity competitive binder of wild-type (WT) and mutant AR with proven efficacy in F877L mutant mice models. The drug is currently being studied in a phase I trial and is enrolling for the dose-expansion phase including patients with an F877L mutation [50,51].…”

Section: Activating Mutations In Ar 321 Ar Point Mutationsmentioning

confidence: 99%

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Jacob

Raj

Allison

et al. 2021

Cancers

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“…Ketoconazole has also been shown to inhibit enzymes important for testosterone synthesis 194 and is under investigation in combination with docetaxel (NCT00212095) 195 . In addition, TRC253, a novel competitive inhibitor of AR has been shown to be an antagonist to wildtype AR as well as all tested AR mutants 196 , including AR F877L, a mutation occurring in the LBD of AR 197 .…”

Section: Second Generation Antiandrogensmentioning

confidence: 99%

ARe we there yet? Understanding androgen receptor signaling in breast cancer

et al. 2020

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The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

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“…It is revealed that GT-0918 as an orally available novel candidate drug acts not only by antagonizing AR but also by downregulating the lipogenesis through inhibiting the expression of ATP citrate lyase (ACL), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN), and sterol regulatory element-binding protein-1 (SREBP-1). , The coinhibition of AR signaling pathway and lipogenesis process confers GT-0918 more promising prospectus to overcome drug resistance and benefit patients’ survival. TRC-253, known as JNJ-63576253, is a novel, orally available novel candidate drug that has completed phase II/A clinical trial in Nov, 2020 . As a lucrative pan-inhibitor against a series of mutant ARs as well as wild-type ARs, it is promising to be a novel resistance-overcome AR antagonist in the future.…”

Section: Resultsmentioning

confidence: 99%

“…TRC-253, known as JNJ-63576253, is a novel, orally available novel candidate drug that has completed phase II/A clinical trial in Nov, 2020. 30 As a lucrative pan-inhibitor against a series of mutant ARs as well as wild-type ARs, it is promising to be a novel resistance-overcome AR antagonist in the future. Rezvilutamide, known as SHR3680, is a novel candidate drug against AR that has completed phase II/A clinical trials (clinical trial information: NCT02691975) and is proven to be a potent AR antagonist with reduced CNS distribution, thereby decreasing the risk of inducing seizures in patients.…”

Section: Resultsmentioning

confidence: 99%

Cheminformatic Analysis and Machine Learning Modeling to Investigate Androgen Receptor Antagonists to Combat Prostate Cancer

Nantasenamat²,

Kachenton

et al. 2023

ACS Omega

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Prostate cancer (PCa) is a major leading cause of mortality of cancer among males. There have been numerous studies to develop antagonists against androgen receptor (AR), a crucial therapeutic target for PCa. This study is a systematic cheminformatic analysis and machine learning modeling to study the chemical space, scaffolds, structure−activity relationship, and landscape of human AR antagonists. There are 1678 molecules as final data sets. Chemical space visualization by physicochemical property visualization has demonstrated that molecules from the potent/active class generally have a mildly smaller molecular weight (MW), octanol−water partition coefficient (log P), number of hydrogen-bond acceptors (nHA), number of rotatable bonds (nRot), and topological polar surface area (TPSA) than molecules from intermediate/inactive class. The chemical space visualization in the principal component analysis (PCA) plot shows significant overlapping distributions between potent/active class molecules and intermediate/inactive class molecules; potent/active class molecules are intensively distributed, while intermediate/inactive class molecules are widely and sparsely distributed. Murcko scaffold analysis has shown low scaffold diversity in general, and scaffold diversity of potent/active class molecules is even lower than intermediate/inactive class molecules, indicating the necessity for developing molecules with novel scaffolds. Furthermore, scaffold visualization has identified 16 representative Murcko scaffolds. Among them, scaffolds 1, 2, 3, 4, 7, 8, 10, 11, 15, and 16 are highly favorable scaffolds due to their high scaffold enrichment factor values. Based on scaffold analysis, their local structure−activity relationships (SARs) were investigated and summarized. In addition, the global SAR landscape was explored by quantitative structure−activity relationship (QSAR) modelings and structure−activity landscape visualization. A QSAR classification model incorporating all of the 1678 molecules stands out as the best model from a total of 12 candidate models for AR antagonists (built on PubChem fingerprint, extra trees algorithm, accuracy for training set: 0.935, 10-fold cross-validation set: 0.735 and test set: 0.756). Deeper insights into the structure−activity landscape highlighted a total of seven significant activity cliff (AC) generators (ChEMBL molecule IDs : 160257, 418198, 4082265, 348918, 390728, 4080698, and 6530), which provide valuable SAR information for medicinal chemistry. The findings in this study provide new insights and guidelines for hit identification and lead optimization for the development of novel AR antagonists.

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An open label phase 1/2A study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer.

Cited by 3 publications

References 0 publications

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

ARe we there yet? Understanding androgen receptor signaling in breast cancer

Cheminformatic Analysis and Machine Learning Modeling to Investigate Androgen Receptor Antagonists to Combat Prostate Cancer

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