Development of 2-(5,6,7-Trifluoro-1<i>H</i>-Indol-3-yl)-quinoline-5-carboxamide as a Potent, Selective, and Orally Available Inhibitor of Human Androgen Receptor Targeting Its Binding Function-3 for the Treatment of Castration-Resistant Prostate Cancer

Leblanc, Éric; Ban, Fuqiang; Cavga, Ayşe Derya; Lawn, Sam; Huang, Chia-Chi Flora; Mohan, Sankar; Chang, Matthew E.K.; Flory, Mark R.; Ghaidi, Fariba; Lingadahalli, Shreyas; Chen, Gang; Yu, Ivan Pak Lok; Morin, Hélène; Lallous, Nada; Gleave, Martin; Mohammed, Hisham; Young, Robert N.; Rennie, Paul S.; Lack, Nathan A.; Cherkasov, Artem

doi:10.1021/acs.jmedchem.1c00681

Cited by 10 publications

(7 citation statements)

References 42 publications

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“…Gene therapy targets not only protein-coding genes but also long non-coding RNAs [74] and microRNAs [75]. PCa FDA-approved therapies also include inhibitors of the androgen receptor signaling, such as enzalutamide [76,77] and darolutamide [78,79]. However, the endless diversity and the strong impact of certain individual characteristics on the PCa progression and treatment outcomes raise serious doubts about the value of such "good-for-everybody" targeted therapies, refocusing the research on personalized solutions.…”

Section: Discussionmentioning

confidence: 99%

Personalized 3-Gene Panel for Prostate Cancer Target Therapy

Iacobaş

2022

CIMB

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Many years and billions spent for research did not yet produce an effective answer to prostate cancer (PCa). Not only each human, but even each cancer nodule in the same tumor, has unique transcriptome topology. The differences go beyond the expression level to the expression control and networking of individual genes. The unrepeatable heterogeneous transcriptomic organization among men makes the quest for universal biomarkers and “fit-for-all” treatments unrealistic. We present a bioinformatics procedure to identify each patient’s unique triplet of PCa Gene Master Regulators (GMRs) and predict consequences of their experimental manipulation. The procedure is based on the Genomic Fabric Paradigm (GFP), which characterizes each individual gene by the independent expression level, expression variability and expression coordination with each other gene. GFP can identify the GMRs whose controlled alteration would selectively kill the cancer cells with little consequence on the normal tissue. The method was applied to microarray data on surgically removed prostates from two men with metastatic PCas (each with three distinct cancer nodules), and DU145 and LNCaP PCa cell lines. The applications verified that each PCa case is unique and predicted the consequences of the GMRs’ manipulation. The predictions are theoretical and need further experimental validation.

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Section: Discussionmentioning

confidence: 99%

Personalized 3-Gene Panel for Prostate Cancer Target Therapy

Iacobaş

2022

CIMB

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“…Compound 123 has an IC 50 of 11.57 μM in LNCaP, compared with bicalutamide whose IC 50 is 23.79 μM . Compound 124 was identified from virtual screening, and 125 is an orally bioavailable prodrug of 124 . Compound 125 inhibits the PSA level in LNCaP cell line with an IC 50 of 0.66 μM.…”

Section: Nonandrogen Competitive Agentsmentioning

confidence: 99%

Therapeutic Strategies to Target the Androgen Receptor

Xiang

Wang

2022

J. Med. Chem.

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The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

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“…More recent studies have described structural rearrangements involving the AR that result in disruption of the gene and selection of potentially constitutively active transcripts that lack the ligand binding domain 3,4 . AR gene alterations in liquid or tissue biopsies associate with shorter responses to second-line next-generation hormonal treatments 5,6 and new drugs are in development to target aberrant AR [7][8][9] . However, heterogeneity of AR gene alterations across metastases creates a challenge that complicates their utility as a biomarker or therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

Hasan

Cremaschi

Wetterskog³

et al. 2023

Preprint

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Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations and cluster-specific AR gene architectures. Copy number boundaries identified treatment-selected clones with distinct lethal trajectories.

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Development of 2-(5,6,7-Trifluoro-1H-Indol-3-yl)-quinoline-5-carboxamide as a Potent, Selective, and Orally Available Inhibitor of Human Androgen Receptor Targeting Its Binding Function-3 for the Treatment of Castration-Resistant Prostate Cancer

Cited by 10 publications

References 42 publications

Personalized 3-Gene Panel for Prostate Cancer Target Therapy

Personalized 3-Gene Panel for Prostate Cancer Target Therapy

Therapeutic Strategies to Target the Androgen Receptor

Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

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